CN101680026A - Adenylyl cyclases as novel targets for the treatment of infection by eukaryotic pathogens - Google Patents

Adenylyl cyclases as novel targets for the treatment of infection by eukaryotic pathogens Download PDF

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CN101680026A
CN101680026A CN200880008339A CN200880008339A CN101680026A CN 101680026 A CN101680026 A CN 101680026A CN 200880008339 A CN200880008339 A CN 200880008339A CN 200880008339 A CN200880008339 A CN 200880008339A CN 101680026 A CN101680026 A CN 101680026A
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adenylyl cyclase
conditioning agent
patient
pharmaceutical composition
fungi
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L·列文
J·巴克
L·布里苏埃拉
M·平尼西
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Cornell Research Foundation Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

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Abstract

The present invention relates to a method of preventing or treating a disease caused by infection by a eukaryotic pathogen, wherein the method comprises administering an effective amount of a modulator of a eukaryotic pathogen's adenylyl cyclase. The invention also provides pharmaceutical compositions useful for preventing or treating a disease, with the compositions containing a therapeutically effective amount of a modulator of a eukaryotic pathogen's adenylyl cyclase. The invention also provides screening methods for identifying selective modulators of a eukaryotic pathogen's adenylyl cyclase that do not substantially modulate an adenylyl cyclase of the subject. The invention also provides methods for culturing eukaryotic pathogens and methods for inducing the pathogenic state in vitro.

Description

Adenylyl cyclase as the novel target of eukaryotic pathogens treatment of infection
The cross reference of related application
[0001] rights and interests of the claimed following U.S. Provisional Patent Application of the application number: in 60/880,089 of application on January 12nd, 2007.The content of this application is attached to herein by reference.
Invention field
[0002] the present invention relates to by adenylyl cyclase conditioning agent prevention that gives significant quantity or the method for the treatment of the disease that causes by the eukaryotic pathogens infection.The present invention also provides the pharmaceutical composition that can be used for preventing or treating disease, and described composition contains the eukaryotic pathogens adenylyl cyclase conditioning agent for the treatment of significant quantity.The present invention also is provided for identifying the screening method of the selective modulator of eukaryotic pathogens adenylyl cyclase, and described selective modulator can significantly not regulated patient's adenylyl cyclase.The present invention also provides the method for cultivating eukaryotic pathogens and in the method for external evoked pathogenic disease states.
Background of invention
[0003] by bacterium to people's organism, ring-3 ', 5 '-adenylic acid (cAMP) mediation is to the cell response of nutritional condition and the outer condition of born of the same parents.Ring AMP is synthetic by adenosine triphosphate (ATP) by adenylyl cyclase, its be hydrolyzed cAMP and form adenosine 5 '-single phosphoric acid (5 '-AMP) cyclic amp phosphodiesterase diesterase rapid damage.In non-reacted cell, cAMP synthetic basal level and its heating rate balance.The concentration of encircling AMP in the cell can respond extracellular signal and change more than 20 times in very short time.Produce these quick response reasons and be that the activity of adenylyl cyclase is upset, make described molecule synthetic (the static usually) heating rate that overwhelmed that this is normal.
[0004] adenylyl cyclase (AC) is the enzyme of one group of catalysis ATP to cAMP and tetra-sodium transformation.Go out 6 class adenylyl cyclases based on protein sequence and CHARACTERISTICS IDENTIFICATION.I class adenylyl cyclase mainly is present in the enterobacteria.II class adenylyl cyclase comprises pathogenic agent excretory toxin, such as from the edema factor (EF) (it causes anthrax) of Bacillus anthracis (Bacillus anthracis), from the CyaA (pertussal cause) of Bordetella pertussis (Bordetella pertussis) with from the ExoY (cause of multiple ward infection) of Pseudomonas aeruginosa (Pseudomonas aeruginosa).The III class is known maximum group, is made up of the cyclase that exists in bacterium, Archimycetes and eukaryote.The IV fermentoid is present in the archeobacteria biology, also is present in some bacterium, comprises the Yersinia pestis (Yersinia pestis) that produces pestilence.The V class comprises from the dwell adenylyl cyclase of the fertile Salmonella (Prevotella ruminicola) of cud Prey of strict anaerobe.The VI class is present in the root nodule bacterium in the nitrogen-fixing bacteria Etta (Rhizobium etli).There are whole 6 fermentoids in the bacterium, but in eukaryote, only described the enzyme that belongs to the III class.
[0005] in mammalian cell, cAMP is produced by two relevant III class adenylyl cyclase families: stride film adenylyl cyclase (tmAC) and solubility adenylyl cyclase (sAC).The difference of these two families is Subcellular Localization, and in response to different conditioning agents (about summary referring to Kamenetsky etc., J.Mol.Biol.362 volume, 623-39 page or leaf, 2006).The main conditioning agent of tmAC is a heterotrimer G albumen, and it transmits extracellular signal in response to hormonal stimulation through g protein coupled receptor.On the contrary, sAC is regulated by born of the same parents' intracellular bicarbonate salt and calcium.
[0006] in host's pathogenic process, infection biological is excited and makes response to one group of different and dynamic envrionment conditions.Multiple pathogenic agent uses this rapid environment transition as signal, changes its growth and virulence.For example, the intravital CO of people (or animal) 2Concentration (5%CO 2) than atmosphere (0.03%CO 2) 150 times difference arranged.When infective micro-organisms is experienced this difference, but they make their genetic program into a kind of genetic program that is fit within infection host.
Summary of the invention
[0007] on the one hand, the present invention has characterized by the eukaryotic pathogens adenylyl cyclase modulators for treatment that gives the patient treatment amount and has suffered from the method that is infected the patient of the disease that causes by eukaryotic pathogens.
[0008] the present invention also provides by the pathogenic agent adenylyl cyclase modulators for treatment that gives the patient treatment amount and suffers from the method that is infected the patient of the disease that causes by eukaryotic pathogens; wherein the amount of the conditioning agent that is given significantly stops pathogenic agent to become pathogenic disease states by non-pathogenic disease states effectively, and the amount of the pathogenic agent adenylyl cyclase conditioning agent that is perhaps wherein given makes pathogenic agent be replied basically by pathogenic disease states to be non-pathogenic disease states effectively.Prevent that eukaryotic pathogens from entering genetic expression and/or albumen generation that pathogenic disease states comprises that prevention is relevant with morbidity, and preventing the change relevant with pathogenic disease states, microbial film is expressed, germinates, formed to for example form change, alteration of form, toxin generation, virulence factor, pod membrane produces and the growth velocity change.
[0009] the present invention also provides by the pathogenic agent adenylyl cyclase modulators for treatment that gives the patient treatment amount and suffers from the method that is infected the patient of the disease that causes by eukaryotic pathogens, and wherein the conditioning agent of pathogenic agent adenylyl cyclase suppresses the pathogenic agent adenylyl cyclase.In other embodiments, the adenylyl cyclase of described conditioning agent activation pathogenic agent.
[0010] the present invention also provides by the pathogenic agent adenylyl cyclase modulators for treatment that gives the patient treatment amount and suffers from the method that is infected the patient of the disease that causes by eukaryotic pathogens, and wherein pathogenic agent adenylyl cyclase conditioning agent has significant biocidal effect to pathogen infection.In other embodiments, pathogenic agent adenylyl cyclase conditioning agent has significant Biostatic effect to pathogen infection.In certain embodiments, the amount of pathogenic agent adenylyl cyclase conditioning agent can significantly not killed pathogen infection.In other embodiments, the amount of pathogenic agent adenylyl cyclase conditioning agent does not suppress or stops the growth of pathogenic agent.
[0011] the present invention also provides by the pathogenic agent adenylyl cyclase modulators for treatment that gives the patient treatment amount and suffers from the method that is infected the patient of the disease cause by eukaryotic pathogens, and wherein pathogenic agent adenylyl cyclase conditioning agent influences more than one adenylyl cyclase of pathogen infection.The present invention also provides pathogenic agent adenylyl cyclase conditioning agent, and it influences more than one adenylyl cyclase of more than one pathogen infection.
[0012] the present invention also provides by the pathogenic agent adenylyl cyclase modulators for treatment that gives the patient treatment amount and suffers from the method that is infected the patient of the disease that causes by eukaryotic pathogens, and wherein pathogenic agent adenylyl cyclase conditioning agent influences the pathogen infection adenylyl cyclase to CO 2Reaction.In other embodiments, described conditioning agent influences the pathogen infection adenylyl cyclase to HCO 3Reaction.In other embodiments, described conditioning agent influences the reaction of pathogen infection adenylyl cyclase to pH.
[0013] the present invention also provides by the pathogenic agent adenylyl cyclase modulators for treatment that gives the patient treatment amount and suffers from the method that is infected the patient of the disease that causes by eukaryotic pathogens, and wherein pathogenic agent adenylyl cyclase conditioning agent influences III class adenylyl cyclase.
[0014] the present invention also provides by the pathogenic agent adenylyl cyclase modulators for treatment that gives the patient treatment amount and suffers from the method that is infected the patient of the disease that causes by eukaryotic pathogens, and wherein said infection is caused by the pathogenic agent of anti-one or more biocides.
[0015] the present invention also provides by the pathogenic agent adenylyl cyclase modulators for treatment that gives the patient treatment amount and suffers from the method that is infected the patient of the disease that causes by eukaryotic pathogens, and wherein said patient is an eukaryote.In further embodiment, described patient is plant, animal, bird, fish or Mammals.Described patient can also be domestic animal, as ox, pig, sheep, poultry and horse, perhaps can be pet, as dog and cat.
[0016] the present invention also provides by the pathogenic agent adenylyl cyclase modulators for treatment that gives the patient treatment amount and suffers from the method that is infected the patient of the disease that causes by eukaryotic pathogens, and wherein said patient behaves.
[0017] the present invention also provides by the pathogenic agent adenylyl cyclase modulators for treatment that gives the patient treatment amount and suffers from the method that is infected the patient of the disease that causes by eukaryotic pathogens, and wherein pathogenic agent adenylyl cyclase conditioning agent can significantly not suppress patient's adenylyl cyclase.In this embodiment, pathogenic agent adenylyl cyclase conditioning agent is optionally with respect to patient's adenylyl cyclase.Preferably, pathogenic agent adenylyl cyclase conditioning agent is enough to realize therapeutic action to pathogen infection with respect to the selectivity of patient's adenylyl cyclase, and can not regulate patient's adenylyl cyclase toxigenicity.
[0018] the present invention also provides the treatment patient method by the eukaryotic pathogens infection of the mediation of the pathogenic agent adenylyl cyclase among the patient, and described method comprises the adenylyl cyclase of regulating eukaryotic pathogens.
[0019] the present invention also provides the method for the adenylyl cyclase that suppresses eukaryotic pathogens, and described method comprises makes eukaryotic cell contact with the compound of the adenylyl cyclase that suppresses eukaryotic pathogens.
[0020] the present invention also provides by the pathogenic agent adenylyl cyclase modulators for treatment that gives the patient treatment amount and suffers from the method that is infected the patient of the disease that causes by eukaryotic pathogens, and wherein pathogenic agent adenylyl cyclase conditioning agent is selected from small molecules, fit and RNA interfering.
[0021] the present invention also provides by the pathogenic agent adenylyl cyclase modulators for treatment that gives the patient treatment amount and suffers from the method that is infected the patient of the disease that causes by eukaryotic pathogens, and wherein pathogenic agent adenylyl cyclase conditioning agent is selected from one or more compounds that is selected from table 1.
[0022] the present invention also provides by the pathogenic agent adenylyl cyclase modulators for treatment that gives the patient treatment amount and suffers from the method that is infected the patient of the disease that causes by eukaryotic pathogens, and wherein pathogenic agent adenylyl cyclase conditioning agent is selected from catechol estrogen and derivative thereof.
[0023] the present invention also provides the method that treatment is infected the patient of the disease that causes by eukaryotic pathogens, and this method is united pathogenic agent adenylyl cyclase conditioning agent and one or more other therapeutical agents that gives the patient treatment amount.In further embodiment, other therapeutical agent is a biocide.
[0024] on the one hand, the present invention has characterized the method for suffering from the patient of the disease that is caused by fungi infestation by the fungi adenylyl cyclase modulators for treatment that gives the patient treatment amount.
[0025] the present invention also provides the method for suffering from the patient of the disease that is caused by fungi infestation by the fungi adenylyl cyclase modulators for treatment that gives the patient treatment amount; wherein the amount of the conditioning agent that is given prevents significantly that effectively fungi from becoming pathogenic disease states by non-pathogenic disease states, and the amount of the fungi adenylyl cyclase conditioning agent that is perhaps wherein given makes fungi be replied basically by pathogenic disease states to be non-pathogenic disease states effectively.Prevent that fungi from entering genetic expression and/or albumen generation that pathogenic disease states comprises that prevention is relevant with morbidity, and preventing the change relevant with pathogenic disease states, microbial film is expressed, germinates, formed to for example form change, alteration of form, toxin generation, virulence factor, pod membrane produces and the growth velocity change.
[0026] the present invention also provides the method for suffering from the patient of the disease that is caused by fungi infestation by the fungi adenylyl cyclase modulators for treatment that gives the patient treatment amount, and wherein fungi adenylyl cyclase conditioning agent suppresses the fungi adenylyl cyclase.In other embodiments, described conditioning agent activation fungi adenylyl cyclase.
[0027] the present invention also provides the method for suffering from the patient of the disease that is caused by fungi infestation by the fungi adenylyl cyclase modulators for treatment that gives the patient treatment amount, and wherein fungi adenylyl cyclase conditioning agent has significant fungicidal action to fungal infection.In other embodiments, fungi adenylyl cyclase conditioning agent has significant Biostatic effect to fungal infection.In certain embodiments, the amount of fungi adenylyl cyclase conditioning agent can significantly not killed fungal infection.In other embodiments, the amount of fungi adenylyl cyclase conditioning agent does not suppress or stops fungal growth.
[0028] the present invention also provides the method for suffering from the patient of the disease that is caused by fungi infestation by the fungi adenylyl cyclase modulators for treatment that gives the patient treatment amount, and wherein fungi adenylyl cyclase conditioning agent influences more than one adenylyl cyclase of fungal infection.The present invention also provides fungi adenylyl cyclase conditioning agent, and it influences more than one adenylyl cyclase of more than one fungal infections.
[0029] the present invention also provides the method for suffering from the patient of the disease that is caused by fungi infestation by the fungi adenylyl cyclase modulators for treatment that gives the patient treatment amount, and wherein fungi adenylyl cyclase conditioning agent influences the fungi adenylyl cyclase to CO 2Reaction.In other embodiments, described conditioning agent influences the fungi adenylyl cyclase to HCO 3Reaction.In other embodiments, described conditioning agent influences the reaction of fungi adenylyl cyclase to pH.
[0030] the present invention also provides the method for suffering from the patient of the disease that is caused by fungi infestation by the fungi adenylyl cyclase modulators for treatment that gives the patient treatment amount, and wherein said fungi adenylyl cyclase is an III class adenylyl cyclase.
[0031] the present invention also provides the method for suffering from the patient of the disease that is caused by fungi infestation by the fungi adenylyl cyclase modulators for treatment that gives the patient treatment amount, and wherein said infection is caused by the fungi of anti-one or more anti-mycotic agents.
[0032] the present invention also provides the method for suffering from the diseases induced patient of the disease that caused by fungi infestation by the fungi adenylyl cyclase modulators for treatment that gives the patient treatment amount, and wherein said patient is an eukaryote.In further embodiment, described patient is plant, animal, bird, fish or Mammals.Described patient can also be domestic animal, as ox, pig, sheep, poultry and horse, perhaps can be pet, as dog and cat.
[0033] the present invention also provides the method for suffering from the patient of the disease that is caused by fungi infestation by the fungi adenylyl cyclase modulators for treatment that gives the patient treatment amount, and wherein said patient behaves.In another embodiment, described people is the people of immune function depression.For example, the people of described immune function depression can be the people of infected by HIV, the people who carries out chemotherapy, patients with blood cancer, transplanting recipient, the people who accepts immunosuppressive drug, the people who accepts opioid drug or bright the wounded.
[0034] the present invention also provides the method for suffering from the patient of the disease that is caused by fungi infestation by the fungi adenylyl cyclase modulators for treatment that gives the patient treatment amount, and wherein fungi adenylyl cyclase conditioning agent can significantly not suppress patient's adenylyl cyclase.In this embodiment, fungi adenylyl cyclase conditioning agent is optionally with respect to patient's adenylyl cyclase.Preferably, fungi adenylyl cyclase conditioning agent is enough to realize therapeutic action to fungal infection with respect to the selectivity of patient's adenylyl cyclase, and can not regulate patient's adenylyl cyclase toxigenicity.
[0035] the present invention also provides the treatment patient method by the fungi infestation of the mediation of the fungi adenylyl cyclase among the patient, and described method comprises the adenylyl cyclase of regulating fungi.
[0036] the present invention also provides the method that suppresses the fungi adenylyl cyclase, and described method comprises makes eukaryotic cell contact with the compound that suppresses the fungi adenylyl cyclase.
[0037] the present invention also provides the method for suffering from the patient of the disease that is caused by fungi infestation by the fungi adenylyl cyclase modulators for treatment that gives the patient treatment amount, and wherein said fungi adenylyl cyclase conditioning agent is selected from small molecules, fit and RNA interfering.
[0038] the present invention also provides the method for suffering from the patient of the disease that is caused by fungi infestation by the fungi adenylyl cyclase modulators for treatment that gives the patient treatment amount, and wherein said adenylyl cyclase conditioning agent is the derivative of density induction molecule or density induction molecule.In one embodiment, described density induction molecule is the farnesol or derivatives thereof.In another embodiment, described density induction molecule is N-3-oxo-C12 homoserine lactone or derivatives thereof.
[0039] the present invention also provides the method for suffering from the patient of the disease that is caused by fungi infestation by the fungi adenylyl cyclase modulators for treatment that gives the patient treatment amount, and wherein said fungi adenylyl cyclase conditioning agent is selected from catechol estrogen and derivative thereof.
[0040] the present invention also provides the method for suffering from the patient of the disease that is caused by fungi infestation by the fungi adenylyl cyclase modulators for treatment that gives the patient treatment amount, and wherein said fungi adenylyl cyclase conditioning agent is selected from the compound that one or more are selected from table 1.
[0041] the present invention also provides the method for suffering from the patient of the disease that is caused by fungi infestation by the fungi adenylyl cyclase modulators for treatment that gives the patient treatment amount; the amount of the adenylyl cyclase inhibitor that is wherein given significantly stops fungi to become thread state by non-thread state effectively, and the amount of the adenylyl cyclase inhibitor that is perhaps wherein given makes fungi be replied basically by thread state to be non-thread state effectively.
[0042] the present invention also provides the method for suffering from the patient of the disease that is caused by fungi infestation by the fungi adenylyl cyclase modulators for treatment that gives the patient treatment amount, and wherein said infection is the infection of the surface, skin, subcutaneous and/or system.
[0043] the present invention also provides the method for suffering from the patient of the disease that is caused by fungi infestation by the fungi adenylyl cyclase modulators for treatment that gives the patient treatment amount, and wherein said fungi is selected from yeast and mould.
[0044] the present invention also provides the method for suffering from the patient of the disease that is caused by fungi infestation by the fungi adenylyl cyclase modulators for treatment that gives the patient treatment amount, and wherein said fungi is from being selected from following genus: Candida (Candida); genera cryptococcus (Cryptococcus); Filobasidiella (Filobasidiella); Geotrichum (Geotrichum); Issatchenkia (Issatchenkia); Malassezia (Malassezia); Pichia (Pichia); pneumocystis (Pneumocystis); Rhodotorula (Rhodotorula); Trichosporon (Trichosporon); absidia (Absidia); Ajellomyces (Ajellomyces); Arthroderma (Arthroderma); Eurotium (Aspergillus); Blastomyces (Blastomyces); Cladosporium (Cladophialophora); Coccidioides (Coccidioides); Epidermophyton (Epidermophyton); entomophthora belongs to (Entomophthorales); Exophiala (Exophiala); Fonsecaea (Fonsecaea); fusarium (Fusarium); tissue milk Pseudomonas (Histoplasma); the mould genus of He De (Hortaea); Madurella (Madurella); Microsporon (Microsporum); mucor (Mucor); Nectria (Nectria); paecilomyces (Paecilomyces); blastomyces brasiliensis belongs to (Paracoccidioides); Penicillium (Penicillium); the swollen Pseudomonas (Pseudallescheria) of foot; Rhizopus (Rhizopus); match many spores Pseudomonas (Scedosporium); Sporothrix (Sporothrix) and Trichophyton (Trichophyton).
[0045] the present invention also provides the method for suffering from the patient of the disease that is caused by fungi infestation by the fungi adenylyl cyclase modulators for treatment that gives the patient treatment amount, and wherein said fungi is selected from: Candida albicans (Candida albicans); Candida glabrata (Candidaglabrata); monilia guilliermondii (Candida guilliermondii); candida krusei (Candidakrusei); Candida parapsilosis (Candida parapsilosis); Oidium tropicale (Candidatropicalis); Cryptococcus neoformans (Cryptococcus neoformans); filobasidiella neoformans (Filobasidiella neoformans); geotrichum candidum (Geotrichum candidum); Issatchenkia orientalis (Issatchenkia orientalis); chaff chlosma (Malassezia furfur); pachydermia chlosma (Malassezia pachydermatis); unusual pichia spp (Pichia anomala); Pichia guilliermondii (Pichia guilliermondii); Pneumocystis carinii (Pneumocystiscarinii); the red torula of viscosity (Rhodotorula mucilaginosa); A Shi trichosporon (Trichosporon asahii); skin shape trichosporon (Trichosporon cutaneum); prepared Chinese ink trichosporon (Trichosporon inkin); viscosity trichosporon (Trichosporon mucoides); absidia corymbifera (Absidia corymbifera); Ajellomyces capsulatus (Ajellomycescapsulatus); dermatitis A Yeluo bacterium (Ajellomyces dermatitidis); benzene is deceived minor details skin bacterium (Arthroderma benhamiae); Arthroderma fulvum (Arthroderma fulvum); Arthroderma gypseum (Arthroderma gypseum); Arthroderma incurvatum (Arthroderma incurvatum); Arthroderma otae (Arthroderma otae); Fan Burui sago joint skin bacterium (Arthrodermavanbreuseghemii); flavus (Aspergillus flavus); Aspergillus fumigatus (Aspergillusfumigatus); aspergillus niger (Aspergillus niger); Blastomyces dermatitidis (Blastomycesdermatitidis); Ka Shi branch spore Saksenaea vasiformis (Cladophialophora carrionii); posadasis spheriforme (Coccidioides immitis); cotton-shaped wheat psoriasis (Epidermophyton floccosum); Exophiala dermatitides (Exophiala dermatitidis); Fonsecaea pedrosoi (Fonsecaea pedrosoi); Fusarinm solani (Fusarium solani); Histoplasma capsulatum (Histoplasma capsulatum); Du Shi histoplasma capsulatum (Histoplasma duboisii); Vinnie Ke Hede mould (Hortaeawerneckii); (Madurella grisae); microsporum canis (Microsporum canis); microsporum fulvum (Microsporum fulvum); microsporon gypseum (Microsporumgypseum); volume branch Mucor (Mucor circinelloides); the red shell of red sphere bundle (Nectriahaematococca); paecilomyces varioti (Paecilomyces variotii); Paracoccidioides brasiliensis (Paracoccidioides brasiliensis); Penicillium marneffei (Penicillium marneffei); the swollen bacterium (Pseudallescheria boydii) of Podbielniak foot; rhizopus arrhizus (Rhizopus arrhizus); Rhizopus oryzae (Rhizopus oryzae); Rhizomucor pusillus (Rhizomucor pusillus); most advanced and sophisticated match many spores (Scedosporium apiospermum); Split-gill (Schizophyllum commune); Sporothrix schenckii (Sporothrix schenckii); alpha fungus (Trichophytonmentagrophytes); trichophyton (Trichophyton rubrum) and Trichophyton verrucosum (Trichophyton verrucosum).
[0046] in a preferred embodiment; the present invention also provides the method for suffering from the patient of the disease that is caused by fungi infestation by the fungi adenylyl cyclase modulators for treatment that gives the patient treatment amount, and wherein said fungi is selected from Candida albicans (Candida albicans); Candida glabrata (Candida glabrata); Cryptococcus neoformans (Cryptococcus neoformans); Aspergillus fumigatus (Aspergillus fumigatus); Coccidioides (Coccidioides); tissue milk Pseudomonas (Histoplasma); blastomycete (Blastomyces) and blastomyces brasiliensis (Paracoccidioides).
[0047] the present invention also provides the patient's of the disease that treatment causes by fungi infestation method, and described method is united fungi adenylyl cyclase conditioning agent and one or more other therapeutical agents that gives the patient treatment amount.In further embodiment, described other therapeutical agent is an anti-mycotic agent.
[0048] on the one hand, the present invention has characterized the method for suffering from the patient of the disease that is caused by protozoal infections by the protozoon adenylyl cyclase modulators for treatment that gives the patient treatment amount.
[0049] the present invention also provides the method for suffering from the patient of the disease that is caused by protozoal infections by the protozoon adenylyl cyclase modulators for treatment that gives the patient treatment amount; wherein the amount of the conditioning agent that is given significantly stops protozoon to become pathogenic disease states by non-pathogenic disease states effectively, and the amount of the protozoon adenylyl cyclase conditioning agent that is perhaps wherein given makes protozoon be replied basically by pathogenic disease states to be non-pathogenic disease states effectively.Prevent that protozoon from entering genetic expression and/or albumen generation that pathogenic disease states comprises that prevention is relevant with morbidity, and preventing the change relevant with pathogenic disease states, for example form change, alteration of form, toxin generation, virulence factor are expressed, germinate, are formed microbial film, excystation and growth velocity and change.
[0050] the present invention also provides the method for suffering from the patient of the disease that is caused by protozoal infections by the protozoon adenylyl cyclase modulators for treatment that gives the patient treatment amount, and wherein said protozoon adenylyl cyclase conditioning agent suppresses the protozoon adenylyl cyclase.In other embodiments, described conditioning agent activation protozoon adenylyl cyclase.
[0051] the present invention also provides the method for suffering from the patient of the disease that is caused by protozoal infections by the protozoon adenylyl cyclase modulators for treatment that gives the patient treatment amount, and wherein said protozoon adenylyl cyclase conditioning agent significantly kills and infects protozoon.In other embodiments, pathogenic agent adenylyl cyclase conditioning agent has significant Biostatic effect to infecting protozoon.In certain embodiments, the amount of protozoon adenylyl cyclase conditioning agent can significantly not killed and be infected protozoon.In other embodiments, the amount of protozoon adenylyl cyclase conditioning agent does not suppress or stops protozoic growth.
[0052] the present invention also provides the method for suffering from the patient of the disease that is caused by protozoal infections by the protozoon adenylyl cyclase modulators for treatment that gives the patient treatment amount, and protozoic more than one adenylyl cyclase is infected in the influence of wherein said protozoon adenylyl cyclase conditioning agent.The present invention also provides protozoon adenylyl cyclase conditioning agent, and it influences protozoic more than one the adenylyl cyclase of more than one infection.
[0053] the present invention also provides the method for suffering from the patient of the disease that is caused by protozoal infections by the protozoon adenylyl cyclase modulators for treatment that gives the patient treatment amount, and wherein said protozoon adenylyl cyclase conditioning agent influences the protozoon adenylyl cyclase to CO 2Reaction.In other embodiments, described conditioning agent influences the protozoon adenylyl cyclase to HCO 3Reaction.In other embodiments, described conditioning agent influences the reaction of protozoon adenylyl cyclase to pH.
[0054] the present invention also provides the method for suffering from the patient of the disease that is caused by protozoal infections by the protozoon adenylyl cyclase modulators for treatment that gives the patient treatment amount, and wherein said protozoon adenylyl cyclase is an III class adenylyl cyclase.
[0055] the present invention also provides the method for suffering from the patient of the disease that is caused by protozoal infections by the protozoon adenylyl cyclase modulators for treatment that gives the patient treatment amount, and wherein said infection is caused by the protozoon of anti-one or more antiprotozoals.
[0056] the present invention also provides the method for suffering from the patient of the disease that is caused by protozoal infections by the protozoon adenylyl cyclase modulators for treatment that gives the patient treatment amount, and wherein said patient is an eukaryote.In further embodiment, described patient is plant, animal, bird, fish or Mammals.Described patient can also be domestic animal, as ox, pig, sheep, poultry and horse, perhaps can be pet, as dog and cat.
[0057] the present invention also provides the method for suffering from the patient of the disease that is caused by protozoal infections by the protozoon adenylyl cyclase modulators for treatment that gives the patient treatment amount, and wherein said patient behaves.In another embodiment, described people is the people of immune function depression.For example, the people of described immune function depression can be the people of infected by HIV, the people who carries out chemotherapy, patients with blood cancer, transplanting recipient, the people who accepts immunosuppressive drug, the people who accepts opioid drug or bright the wounded.
[0058] the present invention also provides the method for suffering from the patient of the disease that is caused by protozoal infections by the protozoon adenylyl cyclase modulators for treatment that gives the patient treatment amount, and wherein protozoon adenylyl cyclase conditioning agent can significantly not suppress patient's adenylyl cyclase.In this embodiment, protozoon adenylyl cyclase conditioning agent is optionally with respect to patient's adenylyl cyclase.Preferably, protozoon adenylyl cyclase conditioning agent is enough to realize to infecting protozoic therapeutic action with respect to the selectivity of patient's adenylyl cyclase, and can not regulate patient's adenylyl cyclase toxigenicity.
[0059] the present invention also provides the treatment patient method by the protozoal infections of the mediation of the protozoon adenylyl cyclase among the patient, and described method comprises regulates protozoic adenylyl cyclase.
[0060] the present invention also provides the method that suppresses the protozoon adenylyl cyclase, and described method comprises makes eukaryotic cell contact with the compound that suppresses the protozoon adenylyl cyclase.
[0061] the present invention also provides the method for suffering from the patient of the disease that is caused by protozoal infections by the protozoon adenylyl cyclase modulators for treatment that gives the patient treatment amount, and wherein said protozoon adenylyl cyclase conditioning agent is selected from small molecules, fit and RNA interfering.
[0062] the present invention also provides the method for suffering from the patient of the disease that is caused by protozoal infections by the protozoon adenylyl cyclase modulators for treatment that gives the patient treatment amount, and wherein said protozoon adenylyl cyclase conditioning agent is selected from catechol estrogen and derivative thereof.
[0063] the present invention also provides the method for suffering from the patient of the disease that is caused by protozoal infections by the protozoon adenylyl cyclase modulators for treatment that gives the patient treatment amount, and wherein said protozoon adenylyl cyclase conditioning agent is selected from the compound that one or more are selected from table 1.
[0064] the present invention also provides the method for suffering from the patient of the disease that is caused by protozoal infections by the protozoon adenylyl cyclase modulators for treatment that gives the patient treatment amount, and wherein said protozoon is selected from rhizopodium Piroplasmea, Ciliata, Flagellata and sporozoa.
[0065] the present invention also provides the method for suffering from the patient of the disease that is caused by protozoal infections by the protozoon adenylyl cyclase modulators for treatment that gives the patient treatment amount, and wherein said protozoon is selected from Gregarinia, Coccidia, Haemocytozoa and Piroplasmida.
[0066] the present invention also provides the method for suffering from the patient of the disease that is caused by protozoal infections by the protozoon adenylyl cyclase modulators for treatment that gives the patient treatment amount, and wherein said protozoon is selected from: Acanthamoeba castellanii (Acanthamoeba castellanii); two bud babesias (Babesia bigemina); babesia canis (Babesia canis); separate babesia (Babesia divergens); vole babesia (Babesia microti); balantidium Coli (Balantidium coli); Bei Shi shellfish promise sporozoite (Besnoitia besnoiti); cryptosporidium parvum (Cryptosporidium parvum); circle spore coccidia (Cyclospora cayetensis); eimeria tenella (Eimeria acervulina); ox eimeria tenella (Eimeria bovis); Bu Shi eimeria tenella (Eimeria brunetti); carp eimeria tenella (Eimeria carpelli); (Eimeriacyprinorum); nothing left body eimeria tenella (Eimeria irresidua); large-scale eimeria tenella (Eimeria magna); huge eimeria tenella (Eimeria maxima); gentle eimeria tenella (Eimeria mitis); poison eimeria tenella (Eimeria necatrix); Ni Shuerci eimeria tenella (Eimeria nieschulzi); perforation eimeria tenella (Eimeria perforans); method is thought eimeria tenella (Eimeria phasiani); precocious eimeria tenella (Eimeria praecox); liver eimeria tenella (Eimeria stiedae); tender eimeria tenella (Eimeria tenella); cut shape eimeria tenella (Eimeria truncata); (Eimeria zurmii); entamoeba histolytica (Entamoeba histolytica); Lan Shi giardia lamblia (Giardia Lamblia); Leishmania donovani (Leishmania donovani); microsporidium (Microsporidia); Fu Shi Na Geli amoeba (Naeglaria flowleri); plasmodium falciparum (Plasmodium falciparum); malariae (Plasmodium malariae); Plasmodium ovale (Plasmodium ovale); Plasmodium vivax (Plasmodium vivax); Pneumocystis carinii (Pneumocystis carinii); neurone sarcocystis (Sarcocystis neurona); Sarcocystis tenella (Sarcocystis tenella); toxoplasma gondii (Toxoplasma gondii); Trichomonas vaginalis (Trichomonas vaginalis); trypanosoma bocagei (Trypanosoma brucei) and schizotrypanum cruzi (Trypanosoma cruzi).
[0067] the present invention also provides the patient's of the disease that treatment causes by protozoal infections method, and this method is united protozoon adenylyl cyclase conditioning agent and one or more other therapeutical agents that gives the patient treatment amount.In further embodiment, described other therapeutical agent is an antiprotozoal.
[0068] on the one hand, the present invention has characterized by the metazoan adenylyl cyclase modulators for treatment that gives the patient treatment amount and has suffered from the method that is infected the patient of the disease that causes by metazoan.
[0069] the present invention also provides by the metazoan adenylyl cyclase modulators for treatment that gives the patient treatment amount and suffers from the method that is infected the patient of the disease that causes by metazoan; wherein the amount of the conditioning agent that is given significantly stops metazoan to become pathogenic disease states by non-pathogenic disease states effectively, and the amount of the metazoan adenylyl cyclase conditioning agent that is perhaps wherein given makes metazoan be replied basically by pathogenic disease states to be non-pathogenic disease states effectively.Prevent that metazoan from entering genetic expression and/or albumen generation that pathogenic disease states comprises that prevention is relevant with morbidity, and prevent that the change relevant with pathogenic disease states, for example form change, alteration of form, toxin from producing, virulence factor is expressed, germinate, form microbial film and growth velocity changes.
[0070] the present invention also provides by the metazoan adenylyl cyclase modulators for treatment that gives the patient treatment amount and suffers from the method that is infected the patient of the disease that causes by metazoan, and wherein said metazoan adenylyl cyclase conditioning agent suppresses the metazoan adenylyl cyclase.In other embodiments, described conditioning agent activation metazoan adenylyl cyclase.
[0071] the present invention also provides by the metazoan adenylyl cyclase modulators for treatment that gives the patient treatment amount and suffers from the method that is infected the patient of the disease that causes by metazoan, and wherein said metazoan adenylyl cyclase conditioning agent has significant biocidal effect to infecting metazoan.In other embodiments, pathogenic agent adenylyl cyclase conditioning agent has significant Biostatic effect to infecting metazoan.In certain embodiments, the amount of metazoan adenylyl cyclase conditioning agent can significantly not killed the metazoan of infection.In other embodiments, the amount of metazoan adenylyl cyclase conditioning agent does not suppress or stops metazoal growth.
[0072] the present invention also provides by the metazoan adenylyl cyclase modulators for treatment that gives the patient treatment amount and suffers from the method that is infected the patient of the disease cause by metazoan, and metazoal more than one adenylyl cyclase is infected in wherein said metazoan adenylyl cyclase conditioning agent influence.The present invention also provides metazoan adenylyl cyclase conditioning agent, and it influences metazoal more than one the adenylyl cyclase of more than one infection.
[0073] the present invention also provides by the metazoan adenylyl cyclase modulators for treatment that gives the patient treatment amount and suffers from the method that is infected the patient of the disease that causes by metazoan, and wherein said metazoan adenylyl cyclase conditioning agent influences the metazoan adenylyl cyclase to CO 2Reaction.In other embodiments, described conditioning agent influences the metazoan adenylyl cyclase to HCO 3Reaction.In other embodiments, described conditioning agent influences the reaction of metazoan adenylyl cyclase to pH.
[0074] the present invention also provides by the metazoan adenylyl cyclase modulators for treatment that gives the patient treatment amount and suffers from the method that is infected the patient of the disease that causes by metazoan, and wherein said metazoan adenylyl cyclase is an III class adenylyl cyclase.
[0075] the present invention also provides by the metazoan adenylyl cyclase modulators for treatment that gives the patient treatment amount and suffers from the method that is infected the patient of the disease that causes by metazoan, and wherein said infection is caused by the metazoan of anti-one or more anti-metazoan agent.
[0076] the present invention also provides by the metazoan adenylyl cyclase modulators for treatment that gives the patient treatment amount and suffers from the method that is infected the patient of the disease that causes by metazoan, and wherein said patient is an eukaryote.In further embodiment, described patient is plant, animal, bird, fish or Mammals.Described patient can also be domestic animal, as ox, pig, sheep, poultry and horse, perhaps can be pet, as dog and cat.
[0077] the present invention also provides by the metazoan adenylyl cyclase modulators for treatment that gives the patient treatment amount and suffers from the method that is infected the patient of the disease that causes by metazoan, and wherein said patient behaves.In another embodiment, described people is the people of immune function depression.For example, the people of described immune function depression can be the people of infected by HIV, the people who carries out chemotherapy, patients with blood cancer, transplanting recipient, accept immunosuppressive drug the people, accept the people of opioid drug or for burning the wounded.
[0078] the present invention also provides by the metazoan adenylyl cyclase modulators for treatment that gives the patient treatment amount and suffers from the method that is infected the patient of the disease that causes by metazoan, and wherein metazoan adenylyl cyclase conditioning agent can significantly not suppress patient's adenylyl cyclase.In this embodiment, metazoan adenylyl cyclase conditioning agent is optionally with respect to patient's adenylyl cyclase.Preferably, metazoan adenylyl cyclase conditioning agent is enough to realize to infecting metazoal therapeutic action with respect to the selectivity of patient's adenylyl cyclase, and can not regulate patient's adenylyl cyclase toxigenicity.
[0079] the present invention also provides the treatment patient method by the metazoan infection of the mediation of the metazoan adenylyl cyclase among the patient, and described method comprises regulates metazoal adenylyl cyclase.
[0080] the present invention also provides the method that suppresses the metazoan adenylyl cyclase, and described method comprises makes eukaryotic cell contact with the compound that suppresses the metazoan adenylyl cyclase.
[0081] the present invention also provides by the metazoan adenylyl cyclase modulators for treatment that gives the patient treatment amount and suffers from the method that is infected the patient of the disease that causes by metazoan, and wherein said metazoan adenylyl cyclase conditioning agent is selected from small molecules, fit and RNA interfering.
[0082] the present invention also provides by the metazoan adenylyl cyclase modulators for treatment that gives the patient treatment amount and suffers from the method that is infected the patient of the disease that causes by metazoan, and wherein said metazoan adenylyl cyclase conditioning agent is selected from catechol estrogen and derivative thereof.
[0083] the present invention also provides by the metazoan adenylyl cyclase modulators for treatment that gives the patient treatment amount and suffers from the method that is infected the patient of the disease that causes by metazoan, and wherein said metazoan adenylyl cyclase conditioning agent is selected from the compound that one or more are selected from table 1.
[0084] the present invention also provides by the metazoan adenylyl cyclase modulators for treatment that gives the patient treatment amount and suffers from the method that is infected the patient of the disease that causes by metazoan, and wherein said metazoan is selected from nematode, tapeworm and fluke.
[0085] the present invention also provides by the metazoan adenylyl cyclase modulators for treatment that gives the patient treatment amount and suffers from the method that is infected the patient of the disease that causes by metazoan, and wherein said metazoan is selected from taeniasis suis (Taenia solium); taeniasis bovis (Taeniasaginata); fish tapeworm (Diphyllobothrium latum); Echinococcus granulosus (Echniococcus granulosus); schistosomicide (Schistosomiasis); liver fluke (Clonorchis); pinworm (Enterobius); whipworm (Tichuris); roundworm (Ascaris); hookworm (Ancylostoma); quasi-colubriformis (Strongyloides); Trichinella spiralis (Trichinella); Anisakid nematode (Anisakis); Wuchereria (Wuchereria); filaria volvulus (Onchocerca); Loa loa (Loa); dragon nematode (Dracuncululs) and bow roundworm (Toxocara).
[0086] the present invention also provides the method that treatment is infected the patient of the disease that causes by metazoan, and this method is united metazoan adenylyl cyclase conditioning agent and one or more other therapeutical agents that gives the patient treatment amount.In further embodiment, described other therapeutical agent is anti-metazoan agent.
[0087] on the one hand, the present invention has characterized the method that is caused disease by the eukaryotic pathogens adenylyl cyclase conditioning agent prevention patient who gives the patient treatment amount by the eukaryotic pathogens infection.
[0088] the present invention also provides the pathogenic agent adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount to be infected the method that causes disease by eukaryotic pathogens; wherein the amount of the conditioning agent that is given significantly prevents pathogenic agent to become pathogenic disease states by non-pathogenic disease states effectively, and the amount of the pathogenic agent adenylyl cyclase conditioning agent that is perhaps wherein given makes pathogenic agent be replied basically by pathogenic disease states to be non-pathogenic disease states effectively.The prevention eukaryotic pathogens enters genetic expression and/or the albumen generation that pathogenic disease states comprises that prevention is relevant with morbidity, and the prevention change relevant with pathogenic disease states, for example form change, alteration of form, toxin produce, virulence factor is expressed, germinate, form microbial film and growth velocity changes.
[0089] the present invention also provides the pathogenic agent adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount to infect the method for the disease that causes by eukaryotic pathogens, and wherein the conditioning agent of pathogenic agent adenylyl cyclase suppresses the pathogenic agent adenylyl cyclase.In other embodiments, the adenylyl cyclase of described conditioning agent activation pathogenic agent.
[0090] the present invention also provides the pathogenic agent adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount to infect the method for the disease that causes by eukaryotic pathogens, and wherein pathogenic agent adenylyl cyclase conditioning agent has significant biocidal effect to pathogen infection.In other embodiments, pathogenic agent adenylyl cyclase conditioning agent has significant Biostatic effect to pathogen infection.In certain embodiments, the amount of pathogenic agent adenylyl cyclase conditioning agent can significantly not killed pathogen infection.In other embodiments, the amount of pathogenic agent adenylyl cyclase conditioning agent does not suppress or stops the growth of pathogenic agent.
[0091] the present invention also provides the pathogenic agent adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount to infect the method for the disease that causes by eukaryotic pathogens, and wherein pathogenic agent adenylyl cyclase conditioning agent influences more than one adenylyl cyclase of pathogen infection.The present invention also provides pathogenic agent adenylyl cyclase conditioning agent, and it influences more than one adenylyl cyclase of more than one pathogen infection.
[0092] the present invention also provides the pathogenic agent adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount to infect the method for the disease that causes by eukaryotic pathogens, and wherein pathogenic agent adenylyl cyclase conditioning agent influences the pathogen infection adenylyl cyclase to CO 2Reaction.In other embodiments, described conditioning agent influences the pathogen infection adenylyl cyclase to HCO 3Reaction.In other embodiments, described conditioning agent influences the reaction of pathogen infection adenylyl cyclase to pH.
[0093] the present invention also provides the pathogenic agent adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount to infect the method for the disease that causes by eukaryotic pathogens, and wherein pathogenic agent adenylyl cyclase conditioning agent influences III class adenylyl cyclase.
[0094] the present invention also provides the pathogenic agent adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount to infect the method for the disease that causes by eukaryotic pathogens, and wherein said infection is caused by the pathogenic agent of anti-one or more biocides.
[0095] the present invention also provides the pathogenic agent adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount to infect the method for the disease that causes by eukaryotic pathogens, and wherein said patient is an eukaryote.In further embodiment, described patient is plant, animal, bird, fish or Mammals.Described patient can also be domestic animal, as ox, pig, sheep, poultry and horse, perhaps can be pet, as dog and cat.
[0096] the present invention also provides the eukaryotic pathogens adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount to infect the method for the disease that causes by eukaryotic pathogens, and wherein said patient behaves.
[0097] the present invention also provides the eukaryotic pathogens adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount to infect the method for the disease that causes by eukaryotic pathogens, and wherein said pathogenic agent adenylyl cyclase conditioning agent can significantly not suppress patient's adenylyl cyclase.In this embodiment, described pathogenic agent adenylyl cyclase conditioning agent is optionally with respect to patient's adenylyl cyclase.Preferably, pathogenic agent adenylyl cyclase conditioning agent is enough to realize therapeutic action to pathogen infection with respect to the selectivity of patient's adenylyl cyclase, and can not regulate patient's adenylyl cyclase toxigenicity.
[0098] the present invention also provides the prevention patient method by the eukaryotic pathogens infection of the mediation of the pathogenic agent adenylyl cyclase among the patient, and described method comprises the adenylyl cyclase of regulating eukaryotic pathogens.
[0099] the present invention also provides the pathogenic agent adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount to infect the method for the disease that causes by eukaryotic pathogens, and wherein pathogenic agent adenylyl cyclase conditioning agent is selected from small molecules, fit and RNA interfering.
[0100] the present invention also provides the pathogenic agent adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount to infect the method for the disease that causes by eukaryotic pathogens, and wherein pathogenic agent adenylyl cyclase conditioning agent is selected from one or more compounds that is selected from table 1.
[0101] the present invention also provides the pathogenic agent adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount to infect the method for the disease that causes by eukaryotic pathogens, and wherein pathogenic agent adenylyl cyclase conditioning agent is selected from catechol estrogen and derivative thereof.
[0102] the present invention also provides the prevention patient to infect the method for the disease cause by eukaryotic pathogens, and this method is united pathogenic agent adenylyl cyclase conditioning agent and one or more other therapeutical agents that gives the patient treatment amount.In further embodiment, other therapeutical agent is a biocide.
[0103] on the one hand, the present invention has characterized the method for the disease that the fungi adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by fungi infestation.
[0104] the present invention also provides the method for the disease that the fungi adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by fungi infestation; wherein the amount of the conditioning agent that is given prevents significantly that effectively fungi from becoming pathogenic disease states by non-pathogenic disease states, and the amount of the fungi adenylyl cyclase conditioning agent that is perhaps wherein given makes fungi be replied basically by pathogenic disease states to be non-pathogenic disease states effectively.The prevention fungi enters genetic expression and/or the albumen generation that pathogenic disease states comprises that prevention is relevant with morbidity, and prevent that the change relevant with pathogenic disease states, for example form change, alteration of form, toxin from producing, virulence factor is expressed, germinate, form microbial film and growth velocity changes.
[0105] the present invention also provides the method for the disease that the fungi adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by fungi infestation, and wherein fungi adenylyl cyclase conditioning agent suppresses the fungi adenylyl cyclase.In other embodiments, described conditioning agent activation fungi adenylyl cyclase.
[0106] the present invention also provides the method for the disease that the fungi adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by fungi infestation, and wherein fungi adenylyl cyclase conditioning agent has significant fungicidal action to fungal infection.In other embodiments, pathogenic agent adenylyl cyclase conditioning agent has significant Biostatic effect to fungal infection.In certain embodiments, the amount of fungi adenylyl cyclase conditioning agent can significantly not killed fungal infection.In other embodiments, the amount of fungi adenylyl cyclase conditioning agent does not suppress or stops fungal growth.
[0107] the present invention also provides the method for the disease that the fungi adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by fungi infestation, and wherein fungi adenylyl cyclase conditioning agent influences more than one adenylyl cyclase of fungal infection.The present invention also provides fungi adenylyl cyclase conditioning agent, and it influences more than one adenylyl cyclase of more than one fungal infections.
[0108] the present invention also provides the method for the disease that the fungi adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by fungi infestation, and wherein fungi adenylyl cyclase conditioning agent influences the fungi adenylyl cyclase to CO 2Reaction.In other embodiments, described conditioning agent influences the fungi adenylyl cyclase to HCO 3Reaction.In other embodiments, described conditioning agent influences the reaction of fungi adenylyl cyclase to pH.
[0109] the present invention also provides the method for the disease that the fungi adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by fungi infestation, and wherein said fungi adenylyl cyclase is an III class adenylyl cyclase.
[0110] the present invention also provides the method for the disease that the fungi adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by fungi infestation, and wherein said infection is caused by the fungi of anti-one or more anti-mycotic agents.
[0111] the present invention also provides the method for the disease that the fungi adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by fungi infestation, and wherein said patient is an eukaryote.In further embodiment, described patient is plant, animal, bird, fish or Mammals.Described patient can also be domestic animal, as ox, pig, sheep, poultry and horse, perhaps can be pet, as dog and cat.
[0112] the present invention also provides the method for the disease that the fungi adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by fungi infestation, and wherein said patient behaves.In another embodiment, described people is the people of immune function depression.For example, the people of described immune function depression can be the people of infected by HIV, the people who carries out chemotherapy, patients with blood cancer, transplanting recipient, the people who accepts immunosuppressive drug, the people who accepts opioid drug or bright the wounded.
[0113] the present invention also provides the fungi adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount to cause the method for disease by fungi infestation, and wherein fungi adenylyl cyclase conditioning agent can significantly not suppress patient's adenylyl cyclase.In this embodiment, fungi adenylyl cyclase conditioning agent is optionally with respect to patient's adenylyl cyclase.Preferably, fungi adenylyl cyclase conditioning agent is enough to realize therapeutic action to fungal infection with respect to the selectivity of patient's adenylyl cyclase, and can not regulate patient's adenylyl cyclase toxigenicity.
[0114] the present invention also provides the prevention patient method by the fungi infestation of the mediation of the fungi adenylyl cyclase among the patient, and described method comprises the adenylyl cyclase of regulating fungi.
[0115] the present invention also provides the method for the disease that the fungi adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by fungi infestation, and wherein said fungi adenylyl cyclase conditioning agent is selected from small molecules, fit and RNA interfering.
[0116] the present invention also provides the method for the disease that the fungi adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by fungi infestation, and wherein said adenylyl cyclase conditioning agent is the derivative of density induction molecule or density induction molecule.In one embodiment, described density induction molecule is the farnesol or derivatives thereof.In another embodiment, described density induction molecule is N-3-oxo-C12 homoserine lactone or derivatives thereof.
[0117] the present invention also provides the method for the disease that the fungi adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by fungi infestation, and wherein said fungi adenylyl cyclase conditioning agent is selected from catechol estrogen and derivative thereof.
[0118] the present invention also provides the method for the disease that the fungi adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by fungi infestation, and wherein said fungi adenylyl cyclase conditioning agent is selected from the compound that one or more are selected from table 1.
[0119] the present invention also provides the method for the disease that the fungi adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by fungi infestation; the amount of the adenylyl cyclase inhibitor that is wherein given significantly stops fungi to become thread state by non-thread state effectively, and the amount of the adenylyl cyclase inhibitor that is perhaps wherein given makes fungi be replied basically by thread state to be non-thread state effectively.
[0120] the present invention also provides the method for the disease that the fungi adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by fungi infestation, and wherein said infection be the infection of surperficial, skin, subcutaneous and/or system.
[0121] the present invention also provides the method for the disease that the fungi adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by fungi infestation, and wherein said fungi is selected from yeast and mould.
[0122] the present invention also provides the method for the disease that the fungi adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by fungi infestation, and wherein said fungi is from being selected from following genus: Candida (Candida); genera cryptococcus (Cryptococcus); Filobasidiella (Filobasidiella); Geotrichum (Geotrichum); Issatchenkia (Issatchenkia); Malassezia (Malassezia); Pichia (Pichia); pneumocystis (Pneumocystis); Rhodotorula (Rhodotorula); Trichosporon (Trichosporon); absidia (Absidia); Ajellomyces (Ajellomyces); Arthroderma (Arthroderma); Eurotium (Aspergillus); Blastomyces (Blastomyces); Cladosporium (Cladophialophora); Coccidioides (Coccidioides); Epidermophyton (Epidermophyton); entomophthora belongs to (Entomophthorales); Exophiala (Exophiala); Fonsecaea (Fonsecaea); fusarium (Fusarium); tissue milk Pseudomonas (Histoplasma); the mould genus of He De (Hortaea); Madurella (Madurella); Microsporon (Microsporum); mucor (Mucor); Nectria (Nectria); paecilomyces (Paecilomyces); blastomyces brasiliensis belongs to (Paracoccidioides); Penicillium (Penicillium); the swollen Pseudomonas (Pseudallescheria) of foot; Rhizopus (Rhizopus); match many spores Pseudomonas (Scedosporium); Sporothrix (Sporothrix) and Trichophyton (Trichophyton).
[0123] the present invention also provides the method for the disease that the fungi adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by fungi infestation, and wherein said fungi is selected from: Candida albicans (Candida albicans); Candida glabrata (Candida glabrata); monilia guilliermondii (Candida guilliermondii); candida krusei (Candida krusei); Candida parapsilosis (Candida parapsilosis); Oidium tropicale (Candida tropicalis); Cryptococcus neoformans (Cryptococcus neoformans); filobasidiella neoformans (Filobasidiellaneoformans); geotrichum candidum (Geotrichum candidum); Issatchenkia orientalis (Issatchenkia orientalis); chaff chlosma (Malassezia furfur); pachydermia chlosma (Malassezia pachydermatis); unusual pichia spp (Pichia anomala); Pichia guilliermondii (Pichia guilliermondii); Pneumocystis carinii (Pneumocystiscarinii); the red torula of viscosity (Rhodotorula mucilaginosa); A Shi trichosporon (Trichosporon asahii); skin shape trichosporon (Trichosporon cutaneum); prepared Chinese ink trichosporon (Trichosporon inkin); viscosity trichosporon (Trichosporon mucoides); absidia corymbifera (Absidia corymbifera); Ajellomyces capsulatus (Ajellomycescapsulatus); dermatitis A Yeluo bacterium (Ajellomyces dermatitidis); benzene is deceived minor details skin bacterium (Arthroderma benhamiae); Arthroderma fulvum (Arthroderma fulvum); Arthroderma gypseum (Arthroderma gypseum); Arthroderma incurvatum (Arthroderma incurvatum); Arthroderma otae (Arthroderma otae); Fan Burui sago joint skin bacterium (Arthrodermavanbreuseghemii); flavus (Aspergillus flavus); Aspergillus fumigatus (Aspergillusfumigatus); aspergillus niger (Aspergillus niger); Blastomyces dermatitidis (Blastomycesdermatitidis); Ka Shi branch spore Saksenaea vasiformis (Cladophialophora carrionii); posadasis spheriforme (Coccidioides immitis); cotton-shaped wheat psoriasis (Epidermophyton floccosum); Exophiala dermatitides (Exophiala dermatitidis); Fonsecaea pedrosoi (Fonsecaea pedrosoi); Fusarinm solani (Fusarium solani); Histoplasma capsulatum (Histoplasma capsulatum); Du Shi histoplasma capsulatum (Histoplasma duboisii); Vinnie Ke Hede mould (Hortaeawerneckii); (Madurella grisae); microsporum canis (Microsporum canis); microsporum fulvum (Microsporum fulvum); microsporon gypseum (Microsporumgypseum); volume branch Mucor (Mucor circinelloides); the red shell of red sphere bundle (Nectriahaematococca); paecilomyces varioti (Paecilomyces variotii); Paracoccidioides brasiliensis (Paracoccidioides brasiliensis); Penicillium marneffei (Penicillium marneffei); the swollen bacterium (Pseudallescheria boydii) of Podbielniak foot; rhizopus arrhizus (Rhizopus arrhizus); Rhizopus oryzae (Rhizopus oryzae); Rhizomucor pusillus (Rhizomucor pusillus); most advanced and sophisticated match many spores (Scedosporium apiospermum); Split-gill (Schizophyllum commune); Sporothrix schenckii (Sporothrix schenckii); alpha fungus (Trichophytonmentagrophytes); trichophyton (Trichophyton rubrum) and Trichophyton verrucosum (Trichophyton verrucosum).In preferred embodiments; the present invention also provides the method for suffering from the disease that is caused by fungi infestation by the fungi adenylyl cyclase conditioning agent prevention patient who gives the patient treatment amount, and wherein said fungi is selected from Candida albicans (Candidaalbicans); Candida glabrata (Candida glabrata); Cryptococcus neoformans (Cryptococcusneoformans); Aspergillus fumigatus (Aspergillus fumigatus); Coccidioides (Coccidioides); tissue milk Pseudomonas (Histoplasma); blastomycete (Blastomyces) and blastomyces brasiliensis (Paracoccidioides).
[0124] the present invention also provides the method for the disease that the prevention patient causes by fungi infestation, and this method is united fungi adenylyl cyclase conditioning agent and one or more other therapeutical agents that gives the patient treatment amount.In further embodiment, described other therapeutical agent is an anti-mycotic agent.
[0125] on the one hand, the present invention has characterized the method for the disease that the protozoon adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by protozoal infections.
[0126] the present invention also provides the method for the disease that the protozoon adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by protozoal infections; wherein the amount of the conditioning agent that is given significantly stops protozoon to become pathogenic disease states by non-pathogenic disease states effectively, and the amount of the protozoon adenylyl cyclase conditioning agent that is perhaps wherein given makes protozoon be replied basically by pathogenic disease states to be non-pathogenic disease states effectively.Prevent that protozoon from entering genetic expression and/or albumen generation that pathogenic disease states comprises that prevention is relevant with morbidity, and preventing the change relevant with pathogenic disease states, for example form change, alteration of form, toxin generation, virulence factor are expressed, germinate, are formed microbial film, excystation and growth velocity and change.
[0127] the present invention also provides the method for the disease that the protozoon adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by protozoal infections, and wherein said protozoon adenylyl cyclase conditioning agent suppresses the protozoon adenylyl cyclase.In other embodiments, described conditioning agent activation protozoon adenylyl cyclase.
[0128] the present invention also provides the method for the disease that the protozoon adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by protozoal infections, and wherein said protozoon adenylyl cyclase conditioning agent significantly kills and infects protozoon.In other embodiments, pathogenic agent adenylyl cyclase conditioning agent has significant Biostatic effect to infecting protozoon.In certain embodiments, the amount of protozoon adenylyl cyclase conditioning agent can significantly not killed the protozoon of infection.In other embodiments, the amount of protozoon adenylyl cyclase conditioning agent does not suppress or stops protozoic growth.
[0129] the present invention also provides the method for the disease that the protozoon adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by protozoal infections, and protozoic more than one adenylyl cyclase is infected in wherein said protozoon adenylyl cyclase conditioning agent influence.The present invention also provides protozoon adenylyl cyclase conditioning agent, and it influences protozoic more than one the adenylyl cyclase of more than one infection.
[0130] the present invention also provides the method for the disease that the protozoon adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by protozoal infections, and wherein said protozoon adenylyl cyclase conditioning agent influences the protozoon adenylyl cyclase to CO 2Reaction.In other embodiments, described conditioning agent influences the protozoon adenylyl cyclase to HCO 3Reaction.In other embodiments, described conditioning agent influences the reaction of protozoon adenylyl cyclase to pH.
[0131] the present invention also provides the method for the disease that the protozoon adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by protozoal infections, and wherein said protozoon adenylyl cyclase is an III class adenylyl cyclase.
[0132] the present invention also provides the method for the disease that the protozoon adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by protozoal infections, and wherein said infection is caused by the protozoon of anti-one or more antiprotozoals.
[0133] the present invention also provides the method for the disease that the protozoon adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by protozoal infections, and wherein said patient is an eukaryote.In further embodiment, described patient is plant, animal, bird, fish or Mammals.Described patient can also be domestic animal, as ox, pig, sheep, poultry and horse, perhaps can be pet, as dog and cat.
[0134] the present invention also provides the method for the disease that the protozoon adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by protozoal infections, and wherein said patient behaves.In another embodiment, described people is the people of immune function depression.For example, the people of described immune function depression can be the people of infected by HIV, the people who carries out chemotherapy, patients with blood cancer, transplanting recipient, accept immunosuppressive drug the people, accept the people of opioid drug or for burning the wounded.
[0135] the present invention also provides the method for the disease that the protozoon adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by protozoal infections, and wherein protozoon adenylyl cyclase conditioning agent can significantly not suppress patient's adenylyl cyclase.In this embodiment, protozoon adenylyl cyclase conditioning agent is optionally with respect to patient's adenylyl cyclase.Preferably, protozoon adenylyl cyclase conditioning agent is enough to realize to infecting protozoic therapeutic action with respect to the selectivity of patient's adenylyl cyclase, and can not regulate patient's adenylyl cyclase toxigenicity.
[0136] the present invention also provides the prevention patient method by the protozoal infections of the mediation of the protozoon adenylyl cyclase among the patient, and described method comprises regulates protozoic adenylyl cyclase.
[0137] the present invention also provides the method for the disease that the protozoon adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by protozoal infections, and wherein said protozoon adenylyl cyclase conditioning agent is selected from small molecules, fit and RNA interfering.
[0138] the present invention also provides the method for the disease that the protozoon adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by protozoal infections, and wherein said protozoon adenylyl cyclase conditioning agent is selected from catechol estrogen and derivative thereof.
[0139] the present invention also provides the method for the disease that the protozoon adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by protozoal infections, and wherein said protozoon adenylyl cyclase conditioning agent is selected from the compound that one or more are selected from table 1.
[0140] the present invention also provides the method for the disease that the protozoon adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by protozoal infections, and wherein said protozoon is selected from rhizopodium Piroplasmea, Ciliata, Flagellata and sporozoa.
[0141] the present invention also provides the method for the disease that the protozoon adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by protozoal infections, and wherein said protozoon is selected from following order: Gregarinia, Coccidia, Haemocytozoa and Piroplasmida.
[0142] the present invention also provides the method for the disease that the protozoon adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount causes by protozoal infections, and wherein said protozoon is selected from: Acanthamoeba castellanii (Acanthamoeba castellanii); two bud babesias (Babesia bigemina); babesia canis (Babesia canis); separate babesia (Babesiadivergens); vole babesia (Babesia microti); balantidium Coli (Balantidiumcoli); Bei Shi shellfish promise sporozoite (Besnoitia besnoiti); cryptosporidium parvum (Cryptosporidium parvum); circle spore coccidia (Cyclospora cayetensis); eimeria tenella (Eimeria acervulina); ox eimeria tenella (Eimeria bovis); Bu Shi eimeria tenella (Eimeria brunetti); carp eimeria tenella (Eimeria carpelli); (Eimeriacyprinorum); nothing left body eimeria tenella (Eimeria irresidua); large-scale eimeria tenella (Eimeria magna); huge eimeria tenella (Eimeria maxima); gentle eimeria tenella (Eimeria mitis); poison eimeria tenella (Eimeria necatrix); Ni Shuerci eimeria tenella (Eimeria nieschulzi); perforation eimeria tenella (Eimeria perforans); method is thought eimeria tenella (Eimeria phasiani); precocious eimeria tenella (Eimeria praecox); liver eimeria tenella (Eimeria stiedae); tender eimeria tenella (Eimeria tenella); cut shape eimeria tenella (Eimeria truncata); (Eimeria zurmii); entamoeba histolytica (Entamoeba histolytica); Lan Shi giardia lamblia (Giardia Lamblia); Leishmania donovani (Leishmania donovani); microsporidium (Microsporidia); Fu Shi Na Geli amoeba (Naeglaria flowleri); plasmodium falciparum (Plasmodium falciparum); malariae (Plasmodium malariae); Plasmodium ovale (Plasmodium ovale); Plasmodium vivax (Plasmodium vivax); Pneumocystis carinii (Pneumocystis carinii); neurone sarcocystis (Sarcocystis neurona); Sarcocystis tenella (Sarcocystis tenella); toxoplasma gondii (Toxoplasma gondii); Trichomonas vaginalis (Trichomonas vaginalis); trypanosoma bocagei (Trypanosoma brucei) and schizotrypanum cruzi (Trypanosoma cruzi).
[0143] the present invention also provides the method for the disease that the prevention patient causes by protozoal infections, and this method is united protozoon adenylyl cyclase conditioning agent and one or more other therapeutical agents that gives the patient treatment amount.In further embodiment, described other therapeutical agent is an antiprotozoal.
[0144] on the one hand, the present invention has characterized the method that is infected the disease that causes by the metazoan adenylyl cyclase conditioning agent prevention patient who gives the patient treatment amount by metazoan.
[0145] the present invention also provides the method that is infected the disease that causes by the metazoan adenylyl cyclase conditioning agent prevention patient who gives the patient treatment amount by metazoan; wherein the amount of the conditioning agent that is given significantly stops metazoan to become pathogenic disease states by non-pathogenic disease states effectively, and the amount of the metazoan adenylyl cyclase conditioning agent that is perhaps wherein given makes metazoan be replied basically by pathogenic disease states to be non-pathogenic disease states effectively.Prevent that metazoan from entering genetic expression and/or albumen generation that pathogenic disease states comprises that prevention is relevant with morbidity, and prevent that the change relevant with pathogenic disease states, for example form change, alteration of form, toxin from producing, virulence factor is expressed, germinate, form microbial film and growth velocity changes.
[0146] the present invention also provides the metazoan adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount to infect the method for the disease that causes by metazoan, and wherein said metazoan adenylyl cyclase conditioning agent suppresses the metazoan adenylyl cyclase.In other embodiments, described conditioning agent activation metazoan adenylyl cyclase.
[0147] the present invention also provides the metazoan adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount to infect the method for the disease that causes by metazoan, and wherein said metazoan adenylyl cyclase conditioning agent significantly kills and infects metazoan.In other embodiments, pathogenic agent adenylyl cyclase conditioning agent has significant Biostatic effect to infecting metazoan.In certain embodiments, the amount of metazoan adenylyl cyclase conditioning agent can significantly not killed the metazoan of infection.In other embodiments, the amount of metazoan adenylyl cyclase conditioning agent does not suppress or stops metazoal growth.
[0148] the present invention also provides the metazoan adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount to infect the method for the disease that causes by metazoan, and metazoal more than one adenylyl cyclase is infected in wherein said metazoan adenylyl cyclase conditioning agent influence.The present invention also provides metazoan adenylyl cyclase conditioning agent, and it influences metazoal more than one the adenylyl cyclase of more than one infection.
[0149] the present invention also provides the metazoan adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount to infect the method for the disease that causes by metazoan, and wherein said metazoan adenylyl cyclase conditioning agent influences the metazoan adenylyl cyclase to CO 2Reaction.In other embodiments, described conditioning agent influences the metazoan adenylyl cyclase to HCO 3Reaction.In other embodiments, described conditioning agent influences the reaction of metazoan adenylyl cyclase to pH.
[0150] the present invention also provides the metazoan adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount to infect the method for the disease that causes by metazoan, and wherein said metazoan adenylyl cyclase is an III class adenylyl cyclase.
[0151] the present invention also provides the metazoan adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount to infect the method for the disease that causes by metazoan, and wherein said infection is caused by the metazoan of anti-one or more anti-metazoan agent.
[0152] the present invention also provides the metazoan adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount to infect the method for the disease that causes by metazoan, and wherein said patient is an eukaryote.In further embodiment, described patient is plant, animal, bird, fish or Mammals.Described patient can also be domestic animal, as ox, pig, sheep, poultry and horse, perhaps can be pet, as dog and cat.
[0153] the present invention also provides the metazoan adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount to infect the method for the disease that causes by metazoan, and wherein said patient behaves.In another embodiment, described people is the people of immune function depression.For example, the people of described immune function depression can be the people of infected by HIV, the people who carries out chemotherapy, patients with blood cancer, transplanting recipient, accept immunosuppressive drug the people, accept the people of opioid drug or for burning the wounded.
[0154] the present invention also provides the metazoan adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount to infect the method for the disease that causes by metazoan, and wherein metazoan adenylyl cyclase conditioning agent can significantly not suppress patient's adenylyl cyclase.In this embodiment, metazoan adenylyl cyclase conditioning agent is optionally with respect to patient's adenylyl cyclase.Preferably, metazoan adenylyl cyclase conditioning agent is enough to realize to infecting metazoal therapeutic action with respect to the selectivity of patient's adenylyl cyclase, and can not regulate patient's adenylyl cyclase toxigenicity.
[0155] the present invention also provides the prevention patient method by the metazoan infection of the mediation of the metazoan adenylyl cyclase among the patient, and described method comprises regulates metazoal adenylyl cyclase.
[0156] the present invention also provides the metazoan adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount to infect the method for the disease that causes by metazoan, and wherein said metazoan adenylyl cyclase conditioning agent is selected from small molecules, fit and RNA interfering.
[0157] the present invention also provides the metazoan adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount to infect the method for the disease that causes by metazoan, and wherein said metazoan adenylyl cyclase conditioning agent is selected from catechol estrogen and derivative thereof.
[0158] the present invention also provides the metazoan adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount to infect the method for the disease that causes by metazoan, and wherein said metazoan adenylyl cyclase conditioning agent is selected from the compound that one or more are selected from table 1.
[0159] the present invention also provides the metazoan adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount to infect the method for the disease that causes by metazoan, and wherein said metazoan is selected from nematode, tapeworm and fluke.
[0160] the present invention also provides the metazoan adenylyl cyclase conditioning agent prevention patient by giving the patient treatment amount to infect the method for the disease that causes by metazoan, and wherein said metazoan is selected from taeniasis suis (Taenia solium); taeniasis bovis (Taenia saginata); fish tapeworm (Diphyllobothrium latum); Echinococcus granulosus (Echniococcusgranulosus); schistosomicide (Schistosomiasis); liver fluke (Clonorchis); pinworm (Enterobius); whipworm (Tichuris); roundworm (Asscaris); hookworm (Ancylostoma); quasi-colubriformis (Strongyloides); Trichinella spiralis (Trichinella); Anisakid nematode (Anisakis); Wuchereria (Wuchereria); filaria volvulus (Onchocerca); Loa loa (Loa); dragon nematode (Dracuncululs) and bow roundworm (Toxocara).
[0161] the present invention also provides the prevention patient to infect the method for the disease cause by metazoan, and this method is united metazoan adenylyl cyclase conditioning agent and one or more other therapeutical agents that gives the patient treatment amount.In further embodiment, described other therapeutical agent is anti-metazoan agent.
[0162] on the one hand, the present invention has characterized the pharmaceutical composition that contains the eukaryotic pathogens adenylyl cyclase conditioning agent for the treatment of significant quantity.
[0163] the present invention also provides the pharmaceutical composition that contains the eukaryotic pathogens adenylyl cyclase conditioning agent for the treatment of significant quantity; wherein the amount of the conditioning agent that is given significantly stops pathogenic agent to become pathogenic disease states by non-pathogenic disease states effectively, and the amount of the pathogenic agent adenylyl cyclase conditioning agent that is perhaps wherein given makes pathogenic agent be replied basically by pathogenic disease states to be non-pathogenic disease states effectively.The prevention eukaryotic pathogens enters genetic expression and/or the albumen generation that pathogenic disease states comprises that prevention is relevant with morbidity, and prevent that the change relevant with pathogenic disease states, for example form change, alteration of form, toxin from producing, virulence factor is expressed, germinate, form microbial film and growth velocity changes.
[0164] the present invention also provides the pharmaceutical composition that contains the eukaryotic pathogens adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein the conditioning agent of pathogenic agent adenylyl cyclase suppresses the pathogenic agent adenylyl cyclase.In other embodiments, the adenylyl cyclase of described conditioning agent activation pathogenic agent.
[0165] the present invention also provides the pharmaceutical composition that contains the eukaryotic pathogens adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein pathogenic agent adenylyl cyclase conditioning agent has significant biocidal effect to pathogen infection.In other embodiments, pathogenic agent adenylyl cyclase conditioning agent has significant Biostatic effect to pathogen infection.In certain embodiments, the amount of pathogenic agent adenylyl cyclase conditioning agent can significantly not killed the pathogenic agent of infection.In other embodiments, the amount of pathogenic agent adenylyl cyclase conditioning agent does not suppress or stops the growth of pathogenic agent.
[0166] the present invention also provides the pharmaceutical composition that contains the eukaryotic pathogens adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein pathogenic agent adenylyl cyclase conditioning agent influences more than one adenylyl cyclase of pathogen infection.The present invention also provides pathogenic agent adenylyl cyclase conditioning agent, and it influences more than one adenylyl cyclase of more than one pathogen infection.
[0167] the present invention also provides the pharmaceutical composition that contains the eukaryotic pathogens adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein pathogenic agent adenylyl cyclase conditioning agent influences the pathogen infection adenylyl cyclase to CO 2Reaction.In other embodiments, described conditioning agent influences the pathogen infection adenylyl cyclase to HCO 3Reaction.In other embodiments, described conditioning agent influences the reaction of pathogen infection adenylyl cyclase to pH.
[0168] the present invention also provides the pharmaceutical composition that contains the eukaryotic pathogens adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein pathogenic agent adenylyl cyclase conditioning agent influences III class adenylyl cyclase.
[0169] the present invention also provides the pharmaceutical composition that contains the pathogenic agent adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said infection is caused by the pathogenic agent of anti-one or more biocides.
[0170] the present invention also provides the pharmaceutical composition that contains the eukaryotic pathogens adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said patient is an eukaryote.In further embodiment, described patient is plant, animal, bird, fish or Mammals.Described patient can also be domestic animal, as ox, pig, sheep, poultry and horse, perhaps can be pet, as dog and cat.
[0171] the present invention also provides the pharmaceutical composition that contains the eukaryotic pathogens adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said patient behaves.
[0172] the present invention also provides the pharmaceutical composition that contains the eukaryotic pathogens adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein pathogenic agent adenylyl cyclase conditioning agent can significantly not suppress patient's adenylyl cyclase.In this embodiment, pathogenic agent adenylyl cyclase conditioning agent is optionally with respect to patient's adenylyl cyclase.Preferably, pathogenic agent adenylyl cyclase conditioning agent is enough to realize therapeutic action to pathogen infection with respect to the selectivity of patient's adenylyl cyclase, and can not regulate patient's adenylyl cyclase toxigenicity.
[0173] the present invention also provides the pharmaceutical composition that contains the eukaryotic pathogens adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein pathogenic agent adenylyl cyclase conditioning agent is selected from small molecules, fit and RNA interfering.
[0174] the present invention also provides the pharmaceutical composition that contains the eukaryotic pathogens adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein pathogenic agent adenylyl cyclase conditioning agent is selected from one or more compounds that is selected from table 1.
[0175] the present invention also provides the pharmaceutical composition that contains the eukaryotic pathogens adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein pathogenic agent adenylyl cyclase conditioning agent is selected from catechol estrogen and derivative thereof.
[0176] the present invention also provides and contains the eukaryotic pathogens adenylyl cyclase conditioning agent for the treatment of significant quantity and the pharmaceutical composition of one or more other therapeutical agents.In further embodiment, described other therapeutical agent is a biocide.
[0177] on the one hand, the present invention has characterized the pharmaceutical composition that contains the fungi adenylyl cyclase conditioning agent for the treatment of significant quantity.
[0178] the present invention also provides the pharmaceutical composition that contains the fungi adenylyl cyclase conditioning agent for the treatment of significant quantity; wherein the amount of the conditioning agent that is given prevents significantly that effectively fungi from becoming pathogenic disease states by non-pathogenic disease states, and the amount of the fungi adenylyl cyclase conditioning agent that is perhaps wherein given makes fungi be replied basically by pathogenic disease states to be non-pathogenic disease states effectively.The prevention fungi enters genetic expression and/or the albumen generation that pathogenic disease states comprises that prevention is relevant with morbidity, and prevent that the change relevant with pathogenic disease states, for example form change, alteration of form, toxin from producing, virulence factor is expressed, germinate, form microbial film and growth velocity changes.
[0179] the present invention also provides the pharmaceutical composition that contains the fungi adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein fungi adenylyl cyclase conditioning agent suppresses the fungi adenylyl cyclase.In other embodiments, described conditioning agent activation fungi adenylyl cyclase.
[0180] the present invention also provides the pharmaceutical composition that contains the fungi adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein fungi adenylyl cyclase conditioning agent has significant fungicidal action to fungal infection.In other embodiments, described fungi adenylyl cyclase conditioning agent has significant Biostatic effect to fungal infection.In certain embodiments, the amount of fungi adenylyl cyclase conditioning agent significantly can not killed the fungi of infection.In other embodiments, the amount of fungi adenylyl cyclase conditioning agent does not suppress or stops fungal growth.
[0181] the present invention also provides the pharmaceutical composition that contains the fungi adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein fungi adenylyl cyclase conditioning agent influences more than one adenylyl cyclase of fungal infection.The present invention also provides fungi adenylyl cyclase conditioning agent, and it influences more than one adenylyl cyclase of more than one fungal infections.
[0182] the present invention also provides the pharmaceutical composition that contains the fungi adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein fungi adenylyl cyclase conditioning agent influences the fungi adenylyl cyclase to CO 2Reaction.In other embodiments, described conditioning agent influences the fungi adenylyl cyclase to HCO 3Reaction.In other embodiments, described conditioning agent influences the reaction of fungi adenylyl cyclase to pH.
[0183] the present invention also provides the pharmaceutical composition that contains the fungi adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said fungi adenylyl cyclase is an III class adenylyl cyclase.
[0184] the present invention also provides the pharmaceutical composition that contains the fungi adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said infection is caused by the fungi of anti-one or more anti-mycotic agents.
[0185] the present invention also provides the pharmaceutical composition that contains the fungi adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said patient is an eukaryote.In further embodiment, described patient is plant, animal, bird, fish or Mammals.Described patient can also be domestic animal, as ox, pig, sheep, poultry and horse, perhaps can be pet, as dog and cat.
[0186] the present invention also provides the pharmaceutical composition that contains the fungi adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said patient behaves.In another embodiment, described people is the people of immune function depression.For example, the people of described immune function depression can be the people of infected by HIV, the people who carries out chemotherapy, patients with blood cancer, transplanting recipient, accept immunosuppressive drug the people, accept the people of opioid drug or for burning the wounded.
[0187] the present invention also provides the pharmaceutical composition that contains the fungi adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein fungi adenylyl cyclase conditioning agent can significantly not suppress patient's adenylyl cyclase.In this embodiment, fungi adenylyl cyclase conditioning agent is optionally with respect to patient's adenylyl cyclase.Preferably, fungi adenylyl cyclase conditioning agent is enough to realize therapeutic action to fungal infection with respect to the selectivity of patient's adenylyl cyclase, and can not regulate patient's adenylyl cyclase toxigenicity.
[0188] the present invention also provides the pharmaceutical composition that contains the fungi adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said fungi adenylyl cyclase conditioning agent is selected from small molecules, fit and RNA interfering.
[0189] the present invention also provides the pharmaceutical composition that contains the fungi adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said adenylyl cyclase conditioning agent is the derivative of density induction molecule or density induction molecule.In one embodiment, described density induction molecule is the farnesol or derivatives thereof.In another embodiment, described density induction molecule is N-3-oxo-C12 homoserine lactone or derivatives thereof.
[0190] the present invention also provides the pharmaceutical composition that contains the fungi adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said fungi adenylyl cyclase conditioning agent is selected from catechol estrogen and derivative thereof.
[0191] the present invention also provides the pharmaceutical composition that contains the fungi adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said fungi adenylyl cyclase conditioning agent is selected from the compound that one or more are selected from table 1.
[0192] the present invention also provides the pharmaceutical composition that contains the fungi adenylyl cyclase conditioning agent for the treatment of significant quantity; the amount of the adenylyl cyclase inhibitor that is wherein given significantly stops fungi to become thread state by non-thread state effectively, and the amount of the adenylyl cyclase inhibitor that is perhaps wherein given makes fungi be replied basically by thread state to be non-thread state effectively.
[0193] the present invention also provides the pharmaceutical composition that contains the fungi adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said fungi infestation is the infection of the surface, skin, subcutaneous and/or system.
[0194] the present invention also provides the pharmaceutical composition that contains the fungi adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said fungi is selected from yeast and mould.
[0195] the present invention also provides the pharmaceutical composition that contains the fungi adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said fungi is from being selected from following genus: Candida (Candida); genera cryptococcus (Cryptococcus); Filobasidiella (Filobasidiella); Geotrichum (Geotrichum); Issatchenkia (Issatchenkia); Malassezia (Malassezia); Pichia (Pichia); pneumocystis (Pneumocystis); Rhodotorula (Rhodotorula); Trichosporon (Trichosporon); absidia (Absidia); Ajellomyces (Ajellomyces); Arthroderma (Arthroderma); Eurotium (Aspergillus); Blastomyces (Blastomyces); Cladosporium (Cladophialophora); Coccidioides (Coccidioides); Epidermophyton (Epidermophyton); entomophthora belongs to (Entomophthorales); Exophiala (Exophiala); Fonsecaea (Fonsecaea); fusarium (Fusarium); tissue milk Pseudomonas (Histoplasma); the mould genus of He De (Hortaea); Madurella (Madurella); Microsporon (Microsporum); mucor (Mucor); Nectria (Nectria); paecilomyces (Paecilomyces); blastomyces brasiliensis belongs to (Paracoccidioides); Penicillium (Penicillium); the swollen Pseudomonas (Pseudallescheria) of foot; Rhizopus (Rhizopus); match many spores Pseudomonas (Scedosporium); Sporothrix (Sporothrix) and Trichophyton (Trichophyton).
[0196] the present invention also provides the pharmaceutical composition that contains the fungi adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said fungi is selected from: Candida albicans (Candidaalbicans); Candida glabrata (Candida glabrata); monilia guilliermondii (Candidaguilliermondii); candida krusei (Candida krusei); Candida parapsilosis (Candidaparapsilosis); Oidium tropicale (Candida tropicalis); Cryptococcus neoformans (Cryptococcus neoformans); filobasidiella neoformans (Filobasidiella neoformans); geotrichum candidum (Geotrichum candidum); Issatchenkia orientalis (Issatchenkia orientalis); chaff chlosma (Malassezia furfur); pachydermia chlosma (Malasseziapachydermatis); unusual pichia spp (Pichia anomala); Pichia guilliermondii (Pichia guilliermondii); Pneumocystis carinii (Pneumocystis carinii); the red torula of viscosity (Rhodotorula mucilaginosa); A Shi trichosporon (Trichosporon asahii); skin shape trichosporon (Trichosporon cutaneum); prepared Chinese ink trichosporon (Trichosporoninkin); viscosity trichosporon (Trichosporon mucoides); absidia corymbifera (Absidiacorymbifera); Ajellomyces capsulatus (Ajellomyces capsulatus); dermatitis A Yeluo bacterium (Ajellomyces dermatitidis); benzene is deceived minor details skin bacterium (Arthroderma benhamiae); Arthroderma fulvum (Arthroderma fulvum); Arthroderma gypseum (Arthroderma gypseum); Arthroderma incurvatum (Arthroderma incurvatum); Arthroderma otae (Arthroderma otae); Fan Burui sago joint skin bacterium (Arthroderma vanbreuseghemii); flavus (Aspergillusflavus); Aspergillus fumigatus (Aspergillus fumigatus); aspergillus niger (Aspergillus niger); Blastomyces dermatitidis (Blastomyces dermatitidis); Ka Shi branch spore Saksenaea vasiformis (Cladophialophoracarrionii); posadasis spheriforme (Coccidioides immitis); cotton-shaped wheat psoriasis (Epidermophyton floccosum); Exophiala dermatitides (Exophiala dermatitidis); Fonsecaea pedrosoi (Fonsecaea pedrosoi); Fusarinm solani (Fusarium solani); Histoplasma capsulatum (Histoplasma capsulatum); Du Shi histoplasma capsulatum (Histoplasmaduboisii); Vinnie Ke Hede mould (Hortaea werneckii); (Madurella grisae); microsporum canis (Microsporum canis); microsporum fulvum (Microsporum fulvum); microsporon gypseum (Microsporum gypseum); volume branch Mucor (Mucorcircinelloides); the red shell of red sphere bundle (Nectria haematococca); paecilomyces varioti (Paecilomyces variotii); Paracoccidioides brasiliensis (Paracoccidioides brasiliensis); Penicillium marneffei (Penicillium marneffei); the swollen bacterium (Pseudallescheriaboydii) of Podbielniak foot; rhizopus arrhizus (Rhizopus arrhizus); Rhizopus oryzae (Rhizopus oryzae); Rhizomucor pusillus (Rhizomucor pusillus); most advanced and sophisticated match many spores (Scedosporium apiospermum); Split-gill (Schizophyllum commune); Sporothrix schenckii (Sporothrix schenckii); alpha fungus (Trichophyton mentagrophytes); trichophyton (Trichophytonrubrum) and Trichophyton verrucosum (Trichophyton verrucosum).In preferred embodiments; the present invention also provides the pharmaceutical composition that contains the fungi adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said fungi is selected from Candida albicans (Candida albicans), Candida glabrata (Candida glabrata), Cryptococcus neoformans (Cryptococcus neoformans), Aspergillus fumigatus (Aspergillus fumigatus), Coccidioides (Coccidioides), tissue milk Pseudomonas (Histoplasma), blastomycete (Blastomyces) and blastomyces brasiliensis (Paracoccidioides).
[0197] the present invention also provides and contains the pharmaceutical composition that the fungi adenylyl cyclase conditioning agent for the treatment of significant quantity is united one or more other therapeutical agents.In further embodiment, described other therapeutical agent is an anti-mycotic agent.
[0198] on the one hand, the present invention has characterized the pharmaceutical composition that contains the protozoon adenylyl cyclase conditioning agent for the treatment of significant quantity.
[0199] the present invention also provides the pharmaceutical composition that contains the protozoon adenylyl cyclase conditioning agent for the treatment of significant quantity; wherein the amount of the conditioning agent that is given significantly stops protozoon to become pathogenic disease states by non-pathogenic disease states effectively, and the amount of the protozoon adenylyl cyclase conditioning agent that is perhaps wherein given makes protozoon be replied basically by pathogenic disease states to be non-pathogenic disease states effectively.Prevent that protozoon from entering genetic expression and/or albumen generation that pathogenic disease states comprises that prevention is relevant with morbidity, and preventing the change relevant with pathogenic disease states, for example form change, alteration of form, toxin generation, virulence factor are expressed, germinate, are formed microbial film, excystation and growth velocity and change.
[0200] the present invention also provides the pharmaceutical composition that contains the protozoon adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said protozoon adenylyl cyclase conditioning agent suppresses the protozoon adenylyl cyclase.In other embodiments, described conditioning agent activation protozoon adenylyl cyclase.
[0201] the present invention also provides the pharmaceutical composition that contains the protozoon adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said protozoon adenylyl cyclase conditioning agent significantly kills and infects protozoon.In other embodiments, pathogenic agent adenylyl cyclase conditioning agent has significant Biostatic effect to infecting protozoon.In certain embodiments, the amount of protozoon adenylyl cyclase conditioning agent can significantly not killed and be infected protozoon.In other embodiments, the amount of protozoon adenylyl cyclase conditioning agent does not suppress or stops protozoic growth.
[0202] the present invention also provides the pharmaceutical composition that contains the protozoon adenylyl cyclase conditioning agent for the treatment of significant quantity, and protozoic more than one adenylyl cyclase is infected in the influence of wherein said protozoon adenylyl cyclase conditioning agent.The present invention also provides protozoon adenylyl cyclase conditioning agent, and it influences protozoic more than one the adenylyl cyclase of more than one infection.
[0203] the present invention also provides the pharmaceutical composition that contains the protozoon adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said protozoon adenylyl cyclase conditioning agent influences the protozoon adenylyl cyclase to CO 2Reaction.In other embodiments, described conditioning agent influences the protozoon adenylyl cyclase to HCO 3Reaction.In other embodiments, described conditioning agent influences the reaction of protozoon adenylyl cyclase to pH.
[0204] the present invention also provides the pharmaceutical composition that contains the protozoon adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said protozoon adenylyl cyclase is an III class adenylyl cyclase.
[0205] the present invention also provides the pharmaceutical composition that contains the protozoon adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said infection is caused by the protozoon of anti-one or more antiprotozoals.
[0206] the present invention also provides the pharmaceutical composition that contains the protozoon adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said patient is an eukaryote.In further embodiment, described patient is plant, animal, bird, fish or Mammals.Described patient can also be domestic animal, as ox, pig, sheep, poultry and horse, perhaps can be pet, as dog and cat.
[0207] the present invention also provides the pharmaceutical composition that contains the protozoon adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said patient behaves.In another embodiment, described people is the people of immune function depression.For example, the people of described immune function depression can be the people of infected by HIV, the people who carries out chemotherapy, patients with blood cancer, transplanting recipient, accept immunosuppressive drug the people, accept the people of opioid drug or for burning the wounded.
[0208] the present invention also provides the pharmaceutical composition that contains the protozoon adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein protozoon adenylyl cyclase conditioning agent can significantly not suppress patient's adenylyl cyclase.In this embodiment, protozoon adenylyl cyclase conditioning agent is optionally with respect to patient's adenylyl cyclase.Preferably, protozoon adenylyl cyclase conditioning agent is enough to realize to infecting protozoic therapeutic action with respect to the selectivity of patient's adenylyl cyclase, and can not regulate patient's adenylyl cyclase toxigenicity.
[0209] the present invention also provides the pharmaceutical composition that contains the protozoon adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said protozoon adenylyl cyclase conditioning agent is selected from small molecules, fit and RNA interfering.
[0210] the present invention also provides the pharmaceutical composition that contains the protozoon adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said protozoon adenylyl cyclase conditioning agent is selected from catechol estrogen and derivative thereof.
[0211] the present invention also provides the pharmaceutical composition that contains the protozoon adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said protozoon adenylyl cyclase conditioning agent is selected from the compound that one or more are selected from table 1.
[0212] the present invention also provides the pharmaceutical composition that contains the protozoon adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said protozoon is selected from rhizopodium Piroplasmea, Ciliata, Flagellata and sporozoa.
[0213] the present invention also provides the pharmaceutical composition that contains the protozoon adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said protozoon is selected from following order: Gregarinia, Coccidia, Haemocytozoa and Piroplasmida.
[0214] the present invention also provides the pharmaceutical composition that contains the protozoon adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said protozoon is selected from: Acanthamoeba castellanii (Acanthamoeba castellanii); two bud babesias (Babesia bigemina); babesia canis (Babesia canis); separate babesia (Babesia divergens); vole babesia (Babesiamicroti); balantidium Coli (Balantidium coli); Bei Shi shellfish promise sporozoite (Besnoitiabesnoiti); cryptosporidium parvum (Cryptosporidium parvum); circle spore coccidia (Cyclospora cayetensis); eimeria tenella (Eimeria acervulina); ox eimeria tenella (Eimeria bovis); Bu Shi eimeria tenella (Eimeria brunetti); carp eimeria tenella (Eimeria carpelli); (Eimeria cyprinorum); nothing left body eimeria tenella (Eimeriairresidua); large-scale eimeria tenella (Eimeria magna); huge eimeria tenella (Eimeriamaxima); gentle eimeria tenella (Eimeria mitis); poison eimeria tenella (Eimerianecatrix); Ni Shuerci eimeria tenella (Eimeria nieschulzi); perforation eimeria tenella (Eimeria perforans); method is thought eimeria tenella (Eimeria phasiani); precocious eimeria tenella (Eimeria praecox); liver eimeria tenella (Eimeria stiedae); tender eimeria tenella (Eimeria tenella); cut shape eimeria tenella (Eimeria truncata); (Eimeriazurmii); entamoeba histolytica (Entamoeba histolytica); Lan Shi giardia lamblia (GiardiaLamblia); Leishmania donovani (Leishmania donovani); microsporidium (Microsporidia); Fu Shi Na Geli amoeba (Naeglaria flowleri); plasmodium falciparum (Plasmodium falciparum); malariae (Plasmodium malariae); Plasmodium ovale (Plasmodium ovale); Plasmodium vivax (Plasmodium vivax); Pneumocystis carinii (Pneumocystis carinii); neurone sarcocystis (Sarcocystis neurona); Sarcocystis tenella (Sarcocystis tenella); toxoplasma gondii (Toxoplasma gondii); Trichomonas vaginalis (Trichomonas vaginalis); trypanosoma bocagei (Trypanosoma brucei) and schizotrypanum cruzi (Trypanosoma cruzi).
[0215] the present invention also provides and contains the pharmaceutical composition that the protozoon adenylyl cyclase conditioning agent for the treatment of significant quantity is united one or more other therapeutical agents.In further embodiment, described other therapeutical agent is an antiprotozoal.
[0216] on the one hand, the present invention has characterized the pharmaceutical composition that contains the metazoan adenylyl cyclase conditioning agent for the treatment of significant quantity.
[0217] the present invention also provides the pharmaceutical composition that contains the metazoan adenylyl cyclase conditioning agent for the treatment of significant quantity; wherein the amount of the conditioning agent that is given significantly stops metazoan to become pathogenic disease states by non-pathogenic disease states effectively, and the amount of the metazoan adenylyl cyclase conditioning agent that is perhaps wherein given makes metazoan be replied basically by pathogenic disease states to be non-pathogenic disease states effectively.Prevent that metazoan from entering genetic expression and/or albumen generation that pathogenic disease states comprises that prevention is relevant with morbidity, and prevent that the change relevant with pathogenic disease states, for example form change, alteration of form, toxin from producing, virulence factor is expressed, germinate, form microbial film and growth velocity changes.
[0218] the present invention also provides the pharmaceutical composition that contains the metazoan adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said metazoan adenylyl cyclase conditioning agent suppresses the metazoan adenylyl cyclase.In other embodiments, described conditioning agent activation metazoan adenylyl cyclase.
[0219] the present invention also provides the pharmaceutical composition that contains the metazoan adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said metazoan adenylyl cyclase conditioning agent significantly kills and infects metazoan.In other embodiments, pathogenic agent adenylyl cyclase conditioning agent has significant Biostatic effect to infecting metazoan.In certain embodiments, the amount of metazoan adenylyl cyclase conditioning agent can significantly not killed and be infected metazoan.In other embodiments, the amount of metazoan adenylyl cyclase conditioning agent does not suppress or stops metazoal growth.
[0220] the present invention also provides the pharmaceutical composition that contains the metazoan adenylyl cyclase conditioning agent for the treatment of significant quantity, and metazoal more than one adenylyl cyclase is infected in the influence of wherein said metazoan adenylyl cyclase conditioning agent.The present invention also provides metazoan adenylyl cyclase conditioning agent, and it influences metazoal more than one the adenylyl cyclase of more than one infection.
[0221] the present invention also provides the pharmaceutical composition that contains the metazoan adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said metazoan adenylyl cyclase conditioning agent influences the metazoan adenylyl cyclase to CO 2Reaction.In other embodiments, described conditioning agent influences the metazoan adenylyl cyclase to HCO 3Reaction.In other embodiments, described conditioning agent influences the reaction of metazoan adenylyl cyclase to pH.
[0222] the present invention also provides the pharmaceutical composition that contains the metazoan adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said metazoan adenylyl cyclase is an III class adenylyl cyclase.
[0223] the present invention also provides the pharmaceutical composition that contains the metazoan adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said infection is caused by the metazoan of anti-one or more anti-metazoan agent.
[0224] the present invention also provides the pharmaceutical composition that contains the metazoan adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said patient is an eukaryote.In further embodiment, described patient is plant, animal, bird, fish or Mammals.Described patient can also be domestic animal, as ox, pig, sheep, poultry and horse, perhaps can be pet, as dog and cat.
[0225] the present invention also provides the pharmaceutical composition that contains the metazoan adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said patient behaves.In another embodiment, described people is the people of immune function depression.For example, the people of described immune function depression can be the people of infected by HIV, the people who carries out chemotherapy, patients with blood cancer, transplanting recipient, accept immunosuppressive drug the people, accept the people of opioid drug or for burning the wounded.
[0226] the present invention also provides the pharmaceutical composition that contains the metazoan adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein metazoan adenylyl cyclase conditioning agent can significantly not suppress patient's adenylyl cyclase.In this embodiment, metazoan adenylyl cyclase conditioning agent is optionally with respect to patient's adenylyl cyclase.Preferably, metazoan adenylyl cyclase conditioning agent is enough to realize to infecting metazoal therapeutic action with respect to the selectivity of patient's adenylyl cyclase, and can not regulate patient's adenylyl cyclase toxigenicity.
[0227] the present invention also provides the pharmaceutical composition that contains the metazoan adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said metazoan adenylyl cyclase conditioning agent is selected from small molecules, fit and RNA interfering.
[0228] the present invention also provides the pharmaceutical composition that contains the metazoan adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said metazoan adenylyl cyclase conditioning agent is selected from catechol estrogen and derivative thereof.
[0229] the present invention also provides the pharmaceutical composition that contains the metazoan adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said metazoan adenylyl cyclase conditioning agent is selected from the compound that one or more are selected from table 1.
[0230] the present invention also provides the pharmaceutical composition that contains the metazoan adenylyl cyclase conditioning agent for the treatment of significant quantity, and wherein said metazoan is selected from taeniasis suis (Taeniasolium); taeniasis bovis (Taenia saginata); fish tapeworm (Diphyllobothriumlatum); Echinococcus granulosus (Echniococcus granulosus); schistosomicide (Schistosomiasis); liver fluke (Clonorchis); pinworm (Enterobius); whipworm (Tichuris); roundworm (Ascaris); hookworm (Ancylostoma); quasi-colubriformis (Strongyloides); Trichinella spiralis (Trichinella); Anisakid nematode (Anisakis); Wuchereria (Wuchereria); filaria volvulus (Onchocerca); Loa loa (Loa); dragon nematode (Dracuncululs) and bow roundworm (Toxocara).
[0231] the present invention also provides and contains the pharmaceutical composition that one or more other therapeutical agents are closed in the metazoan adenylyl cyclase conditioning agent parallel connection for the treatment of significant quantity.In further embodiment, described other therapeutical agent is anti-metazoan agent.
[0232] the present invention also is provided at the method for external control eukaryotic pathogens growth, and described method comprises makes eukaryotic pathogens contact with the conditioning agent of eukaryotic pathogens adenylyl cyclase.In one embodiment, the present invention also is provided at the method for external control fungal growth, and described method comprises makes fungi contact with fungi adenylyl cyclase conditioning agent.In another embodiment, the present invention also is provided at the method for external control protozoon growth, and described method comprises makes protozoon contact with protozoon adenylyl cyclase conditioning agent.In another embodiment, the present invention also is provided at the method for external control metazoan growth, and described method comprises makes metazoan contact with metazoan adenylyl cyclase conditioning agent.
[0233] the present invention also provides the method for the selective modulator of identifying the eukaryotic pathogens adenylyl cyclase; described method comprises: test described conditioning agent at one or more people's adenylyl cyclases; test described conditioning agent at the eukaryotic pathogens adenylyl cyclase, and measure the relative selectivity of described conditioning agent described adenylyl cyclase.In one embodiment, described pathogenic agent is a fungi.In one embodiment, described pathogenic agent is a protozoon.In one embodiment, described pathogenic agent is a metazoan.
[0234] the present invention also provides the method for eukaryote in growth in vitro that be beneficial to, and described method comprises makes described biology contact with the activator of adenylyl cyclase.In one embodiment, described biology is a fungi.In one embodiment, described biology is a protozoon.In one embodiment, described biology is a metazoan.
[0235] the present invention also provides the method for preparing fungal metabolite, and described method is included in the fungi of fermenting in the fermention medium that contains fungi adenylyl cyclase conditioning agent, separates fungal metabolite then from fermention medium.In further embodiment, described fungal metabolite is an enzyme.In another embodiment, described fungal metabolite is a microbiotic.In one embodiment, described fungal metabolite produces by being selected from following fungi: aspergillus citricus (Aspergilluscitricus), aspergillus niger (As.niger), Aspergillus nidulans (As.nidulans), aspergillus oryzae (As.oryzae), flavus (Aspergillus flavus), aspergillus citricus (As.citricus), Aspergillus awamori (As.awamori), terreus (As.terreus), onion aspergillus (A.alliaceus), (A.atroviolaceus), Aspergillus candidus (A.candidus), carbon black aspergillus (A.carbonarius), Aspergillus carneus (A.carneus), rod aspergillus (A.clavatus), Fructus Fici aspergillus (A.ficuum), Aspergillus fumigatus (A.fumigatus), huge aspergillus (A.giganteus), methylene-succinic acid aspergillus (A.itaconicus), Neurospora (A.kiliense), honey aspergillus (A.melleus), Aspergillus ochraceus (A.ochraceus), Aspergillus parasiticus (A.parasiticus), nipa palm aspergillus (A.phoenicis), aspergillus rugulosus (A.rugulosus), saitox aspergillus (A.saitoi), Aspergillus sojae (A.soyae), Aspergillus tamarii (A.tamarii), Aspergillus wentti (A.wentii), short stalk mould (Au.pullulans), peachiness top spore (Acremonium persicinum), branch top spore mould (Acremonium chrysogenum), Calcarisporium arbuscula (Calcarisporium arbuscula), (Chaetomium gracile), endothia parasitica bacterium (Cryphonectria parasitica), Java penicillium (Eupenicillium javanicum), (F.coccophilum), the lanthanum element is to sickle-like bacteria (Fusarium solani), Fusarium oxysporum (Fusariumoxysporum), geotrichum candidum (G.candidum), (Mortiella ramannianua), (Mortierella vinaceae), (Mu.Circinelloides), pink colour bread mould (N.crassa), (Nectria lucida), (Penicillium vitale), (Penicillum decumbens), tangerine ash mould (Penicillium aurantiogriseum), Penicllium chrysogenum (Pe.chrysogenum), (P.amagasakiense), (P.baculatum), Penicillium citrinum (P.citrinum), Du Pont's mould (P.dupontii), penicillium funiculosum (P.funiculosum), Penicillium griseofulvum (P.griseofulvum), (P.griseoroseum), (P.isariiforme), citrus mould (P.italicum), penicillium jensenii (P.jensenii), (P.lilacium), yellowish mould (P.luteum), have a liking for loose mould (P.pinophilum), penicillum requeforti (P.roqueforti), letter mould (P.simplicissimum), not whole mould (P.turbatum), the shape mould (P.vermiculatum) of wriggling, rhizopus arrhizus (R.arrhizus), Rhizopus oryzae (Rhizopus oryzae), rhizopus stolonifer (Rhizop.stolonifer), snow-white head mold (R.niveus), (Rhizomucor miechei), Rhizomucor pusillus (R.pusillus), little spore root Mucor (R.microsporus), rice black root Mucor (R.meihei), Sclerotinia sclerotiorum (Sclerotinialibertiana), long shoot wood mould (T.longibrachiatum), Trichodermareesei (T.reesei), viride (Trichoderma viride), (Tolypocladium geodes), porous wood mould (T.inflatum) and many spores wood mould (Trichoderma polysporum).In one embodiment, the conditioning agent of fungi adenylyl cyclase makes fungi be in thread state basically effectively.In one embodiment, the conditioning agent of fungi adenylyl cyclase makes fungi be in non-thread state basically effectively.In one embodiment, described fungi adenylyl cyclase is CO 2/ HCO 3/ pH responsive type.
Accompanying drawing is described
[0236] Fig. 1. compound K H7, KH7.14 and KH7.15 are to the effect of the growth of blood flow type (trypomastigote) trypanosoma bocagei (Trypansoma brucei).Cell density (the cell/mL) volumetric molar concentration of compound is mapped that uses the Coulter counter to detect.
[0237] Fig. 2 .KH7 compound is to the active effect of adenylyl cyclase of trypanosoma bocagei (Trypansoma brucei) cell lysate.The active amount of passing through the cAMP of generation of adenylyl cyclase detects, and this amount is with the μ M concentration mapping of pmol cAMP/mL to KH7.
Detailed Description Of The Invention
[0238] the invention provides accent by the eucaryon adenylyl cyclase that gives effective dose The method of joint agent prevention or treatment disease.
[0239] adenylyl cyclase is that one group of catalysis ATP changes to cAMP and pyrophosphoric acid Enzyme. 6 class adenylyl cyclases have been identified based on protein sequence and characteristic. I class adenylyl Cyclase mainly is present in the enterobacteria. II class adenylyl cyclase comprises by pathogen secretion Toxin, (it draws such as the edema factor (EF) from Bacillus anthracis (Bacillus anthracis) Play anthrax), from CyaA (one hundred days of Bordetella pertussis (Bordetellapertussis) The cause of coughing) with from ExoY (the multiple institute of Pseudomonas aeruginosa (Pseudomonas aeruginosa) The cause of interior infection). The III class is known maximum group, by at bacterium, Archimycetes and eucaryon The cyclase that exists in the biology forms. The IV fermentoid is present in the archeobacteria biology, also is present in certain In a little bacteriums, comprise the Yersinia pestis (Yersinia pestis) that produces pestilence. V class bag Contain from strict anaerobe a kind of of the fertile Salmonella (Prevotella ruminicola) of cud Prey of dwelling Adenylyl cyclase. The VI class is present in the rhizobium in the azotobacteria Etta (Rhizobium etli). There are whole 6 fermentoids in the bacterium, but in eucaryote, only described the enzyme that belongs to the III class.
[0240] in mammalian cell, cAMP is by two relevant III class adenylyl rings Changing enzyme family produces: stride film adenylyl cyclase (tmAC) and solubility adenylyl cyclase (sAC). The difference of these two families is Subcellular Localization, and in response to different conditioning agents. The main conditioning agent of tmAC is Heterotrimeric G-Protein, and it transmits born of the same parents through g protein coupled receptor External signal. On the contrary, sAC is regulated by born of the same parents' intracellular bicarbonate salt and calcium.
[0241] carbon dioxide (CO2) be the end-product of animal metabolism. At all physiological systems In, owing to have enzyme-carbonic anhydrase, CO2With bicarbonate and pH (H+Concentration) almost be in instant balance, described carbonic anhydrase catalysis carbon dioxide and water is to the quick change of carbonic acid, and is dissociated into proton and bicarbonate ion according to following formula:
Figure A20088000833900831
This reacts spontaneous generation in the aqueous solution, but carries out very slowly. Enzyme-carbonic anhydrase greatly Increased the speed of this reaction.
[0242] in host's pathogenic process, infection biological is challenged, with to one group of difference And dynamic environmental condition is made response. But in a single day the Various Diseases protozoa is evolved at infection host In run into rapid environment transition, just use this transformation as signal, change its growth and poison Power. A kind of such ambient signal that infectious bacteria uses is CO2、HCO 3 -And/or pH The change of concentration. CO in people (or animal) body2Concentration (5%CO2) than atmosphere (0.03% CO2) 150 times difference arranged. Because CO2Level and magnesium hydrogen salt concentration and pH level balance each other, so these infection biologicals in infection host the time, can be experienced the CO that detects2Concentration, HCO3The difference of concentration or pH level.
[0243] is subjected to CO2/HCO 3The cyclase of regulating is to be used in the fungal pathogens preventing from causing The sick clear and definite target of evolution that changes. We confirm, candida albicans and cryptococcus adenylyl cyclase (AC) CO2/HCO 3Responsive type is when they are pressed down by little molecule (general sAC sample AC inhibitor KH7) When processed, the essential Morphological Transitions of falling ill is blocked. Support the basis of our discovery to be, true Bacterium is evolved and the mechanism of regulating they self morbidity is by Antifungi AC. We are nearest Data find that fungi AC is that Candida albicans (Candida albicans) self is used for automatically regulating The target that himself changes. The pathogenic factor of being synthesized by fungi and secreting is regulated the described factor automatically As ' density inductor '. In addition, the bacterium of symbiosis growth is target fungi AC also, with limit Morbidity in the symbiosis ecological niche.
[0244] is subjected to CO2/HCO 3The adenylyl cyclase of regulating is the CO in the parasitic protozoal animal2Chemoreceptor, but its permission is grown in infection biological. We have used specifically Micromolecular inhibitor and activator confirm, are subjected to CO in the plasmodium2/HCO 3The cyclase of regulating is that growth is necessary in red blood cell, and it only is responsible in vitro culture viewed to CO2The experiment dependence. In addition, we have identified selective killing malaria parasitism in red blood cell The lead compound of thing (referring to WO 2005/070419, its by reference integral body be attached to this paper In).
[0245] other eukaryotic pathogens utilizes CO2/HCO 3/ pH-sensitiveness AC regulates Pathogenic. Show that in heredity adenylyl cyclase is primary in other infectivity to virulence factor Expression in the animal is important, and described protozoan comprises trypanosoma bocagei (Trypanosoma Brucei), schizotrypanum cruzi (Trypanosoma cruzi) and Leishmania donovani (Leishmania Donovani). In trypanosome and Leishmania, virulence factor is only the protozoal infections host In time, express, i.e. the high CO of protozoan in their human host of contact2Express during environment, on evolving, predict that the AC in these biologies is CO2/HCO 3/ pH responsive type. With cause malaria The protozoan difference of disease, the CO in trypanosome and Leishmania2/HCO 3/ pH sensitiveness As if AC is optional to growing, but changes harmless commensal into pathogenic giving birth to inducing The Development And Differentiation of thing (being similar to the situation of fungi) is essential. In these cases, inhibitor Expression and secretion by preventing toxin should be effective therapeutic agent, and activator should can be used for mould But intend the growth conditions in the infection host.
Eukaryotic pathogens
[0246] pathogen is the biology that causes disease in another kind of biology. Usually, cause of disease Body is the biology such as bacterium, virus, fungi or parasitic animal and plant such as worm. In each case, Infection biological all utilizes the life of host's body and growth. Eukaryotic pathogens comprises mycota, primary The member of living nature and metazoa circle.
Fungal pathogens
[0247] fungi causes diversified disease in the mankind, comprises aspergillosis, blastogenesis Bacterium disease, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, secondary ball spore Bacterium disease (paracoccidiomycosis), sporotrichosis and zygomycosis. Caused by fungal infection Other diseases comprise chromoblastomycosis, otomycosis, phaeohyphomycosis, nose sporozoite Disease and dermatomycosis (dermatomycoese). Fungal infection (mycosis) can be classified as the surface The superficial growth of skin or hair (only), skin (wherein conk occurs in skin, refers to The skin of first or hair) (being the ringworm of the foot and ringworm), (it is penetrated under the skin subcutaneous infection, and relates to Hypodermis, connective tissue and bone) and system infects, and (wherein the fungal infection internal organ often scatter In whole body).
[0248] aspergillosis is the spectrum of diseases that is caused by the aspergillus member. Mainly contain 3 kinds of tables Existing: allergic bronchopulmonary aspergillosis, lung aspergilloma and invasive aspergillosis. Deciding of respiratory tract It also is common growing. The clinical manifestation of disease and seriousness depend on patient's immune shape usually Attitude. Because such as basic weak property disease, neutropenia, chemotherapy, normal The factors such as the destruction of flora and use antimicrobial and steroids cause host resistance to fall Low, make the patient suffer from easily that Aspergillus is grown surely and/or the invasive disease. Aspergillus is suffering from the bronchus expansion Open, often be insecondary machine among cancer, other mycosis, sarcoid and the phthisical patient Can pathogen. This biology can infect lung, inner ear, the hole of healthy person, but seldom infects healthy Person's eyes.
[0249] blastomycosis is by region dimorphic fungi Blastomyces dermatitidis (Blastomyces Dermatitidis) cause. Fungi mouldly grows in soil as conidiiferous. It is acquired Infection is that conidium is converted into the yeast form after entering lung immediately because suck conidium, Can cause the acute lung diseases that is similar to bacterial pneumonia. Most of blastomycosis was worked as in chronic phase In display, can attack lung, skin, bone, urogenital tract and other organ.
[0250] candidiasis of various ways is modal fungal infection in the people. Beads Pseudomonas can be in the individuality of other side health and the individuality that reduces at function of immune system The middle generation infected. Mycotoruloides can surely be grown (exist and do not cause disease) or infect any body The surface. The invasive candidiasis is called again systemic candidiasis, is a kind of disease collection of complexity Close. The candidiasis of these forms is only in the individuality that function of immune system reduces or some other Can see in the individuality that the defense function of type weakens, and may relate to any biological organs.
[0251] coccidioidomycosis is by dimorphic fungi posadasis spheriforme (Coccidioides Immitis) infection that causes. This disease is endemic, only is in zone, the Western Hemisphere. This disease is quick-fried Occur in after dust storm, earthquake and the shoveling, spore (arthroconidium) looses in these cases Broadcast. Coccidioidomycosis obtains by sucking spore. One enters in the lung, and arthroconidium just is converted into The sphaerocyst that is called " spherule ". ARI is generation in 7-21 days after contact, And usually disappear fast. Yet, infect alternately cause chronic lung disease or scatter meninx, In bone, joint and subcutaneous and the skin histology.
[0252] cryptococcosis refers to by capsule yeast Cryptococcus neoformans (Cryptococcus Neoformans) infection that produces. This infection begins after sucking this biology usually. The primary sense Dye and to keep being positioned in the lung, perhaps can be dispersed in the whole body. Lung carcinoma infects Normally asymptomatic. Yet chronic form can develop the multiple disease damage of generation. In case scatter, Meningitis is exactly common performance. Cryptococcosis is considered to opportunistic infections, and it is mainly attacked The individuality of immune function depression, but also can attack healthy individual.
[0253] histoplasmosis is divided into two class diseases. The more normal finger of this term is by capsule tissue Endochylema bacterium pod membrane mutation (Histoplasma capsulatum var capsulatum) (is also referred to as pod membrane Histoplasma capsulatum (Histoplasma capsulatum)) the histoplasmosis form that causes. This is given birth to The distribution form although also take place in the most normal tuberculosis that causes of thing. Another kind of histoplasmosis is by pod membrane The Du Shi of histoplasma capsulatum mutation (Histoplasma capsulatum var.duboisii) (is also referred to as Du Family name histoplasma capsulatum (Histoplasma duboisii)) causes that it the most often causes skin disease and bone Sick.
[0254] paracoccidioidomycosis refers to by Paracoccidioides brasiliensis (Paracoccidioides Brasiliensis) disease that produces. Infer that sucking the conidium bacterium is to obtain the disease approach. Primary infection Generally asymptomatic. This fungi can keep the dormancy several years in lymph node, manifest afterwards, may Relevant with the immune deficiency of some form. What is interesting is that paracoccidioidomycosis is mainly attacked the male sex With the people more than 30 years old. The not good young type of prognosis seldom takes place. Adult is usually expressed as Pain ulcerative lesion in the mouth. Other clinical manifestation comprises skin lesion, lymphadenopathy, gulps down Pharynx difficulty and hoarse. At last, the clinical condition identical with pulmonary tuberculosis (heating, body also may take place Heavily alleviate and with the productive cough of sputum with blood streaks).
[0255] sporotrichosis refers to by dimorphic fungi Sporothrix schenckii (Sporothrix Schenckii) infection that causes. Sporotrichosis is by obtaining in the direct access skin, and is seldom logical Crossing the suction conidium obtains. Thereby most of situation is invasion and attack skin and hypodermic office Section's disease damage seldom is systematicness performance (if any). The outer sporothrix of modal corium Sick form is osteoarthritis. Can see the disease of lung and the form of distribution, these are usually attacked and exempt from It is individual that epidemic disease suppresses.
[0256] engaging the sick close blood vessel (angioinvasive) that is produced by multiple zygomycete that refers to feels Dye. The most common species that cause this disease are absidia corymbiferas (Absidia corymbifera), small Root Mucor (Rhizomucor pusillus) and Rhizopus arrhizus (Rhizopus arrhizus).
[0257] mucormycosis causes one by the member of Mucoales family (sometimes being Entomophthorales family) As be acute, and fast-developing in weak patient. This disease and acid poisoning diabetic, Underfed children are relevant with the third-degree burn patient. It is also at leukaemia, lymthoma and AIDS Take place among the patient, and in the patient who uses immunosuppressive therapy such as corticosteroid, take place. Should Fungi passes respiratory tract or intestinal mucosa, and also can enter skin by breach. Local disease damage Can develop, diffuse in the blood afterwards, and diffuse into subsequently other organ. These infect warp Often be fatal.
[0258] chromoblastomycosis is a kind of skin and hypodermic chronic local infection, Caused by many different fungies. Disease damage is the also crust of excipuliform, ulcer, can be for flat Flat or protruding 1-3cm. The satellite disease damage can develop into adjacent domain by the lymph diffusion. Mould Disease is accompanied by widely cicatrization location usually. Yet (for example Pei Shi some virulence factor Look mould (Fonsecaea pedrosoi) and Phialophora verrucosa (Phialophora verrucosa)) can loose Cloth is in brain.
[0259] other fungal disease comprises lung pityrosporion ovale tuberculosis (pneumocystis), and it is one Planting the lung that is caused by Pneumocystis carinii (Pneumocystis carinii) infects. This biology is The common disease of the lethal pneumonia among the AIDS patient because of.
[0260] the invention provides by giving the fungi adenylyl cyclase of patient treatment amount Method and the pharmaceutical composition of the disease that conditioning agent prevention and treatment patient are caused by fungal infection, Wherein said fungi is selected from following genus: Mycotoruloides (Candida), Cryptococcus (Cryptococcus), Filobasidiella (Filobasidiella), Geotrichum (Geotrichum), she Sa saccharomyces (Issatchenkia), Malassezia (Malassezia), pichia (Pichia), pneumocystis (Pneumocystis), Rhodotorula (Rhodotorula), trichosporon cutaneum Belong to (Trichosporon), Absidia (Absidia), Ajellomyces (Ajellomyces), joint skin Pseudomonas (Arthroderma), Eurotium (Aspergillus), Blastomyces (Blastomyces), Cladosporium (Cladophialophora), Coccidioides (Coccidioides), Epidermophyton (Epidermophyton), entomophthora belong to (Entomophthorales), Exophiala (Exophiala), Fonsecaea (Fonsecaea), fusarium (Fusarium), tissue milk Pseudomonas (Histoplasma), The mould genus of He De (Hortaea), Madurella (Madurella), Microsporon (Microsporum), Mucor (Mucor), Nectria (Nectria), paecilomyces (Paecilomyces), blastomyces brasiliensis belongs to (Paracoccidioides), Penicillium (Penicillium), the swollen Pseudomonas (Pseudallescheria) of foot, Rhizopus (Rhizopus), match are many Spore Pseudomonas (Scedosporium), Sporothrix (Sporothrix) and Trichophyton (Trichophyton).
[0261] the invention provides by giving the fungi adenylyl cyclase of patient treatment amount Method and the pharmaceutical composition of the disease that conditioning agent prevention and treatment patient are caused by fungal infection, Wherein said fungi is selected from: Candida albicans (Candida albicans), Candida glabrata (Candida glabrata), monilia guilliermondii (Candida guilliermondii), the gentle beads of gram Bacterium (Candida krusei), Candida parapsilosis (Candida parapsilosis), Candida tropicalis (Candida tropicalis), Cryptococcus neoformans (Cryptococcus neoformans), Novel wire are deceived Powder bacterium (Filobasidiella neoformans), geotrichum candidum (Geotrichum candidum), east Her Sa yeast (Issatchenkia orientalis), chaff chlosma (Malassezia furfur), M.pachy dermats (Malassezia pachydermatis), unusual Pichia pastoris (Pichia Anomala), Pichia guilliermondii (Pichia guilliermondii), Pneumocystis carinii (Pneumocystis carinii), Rhodotorula mucilaginosa (Rhodotorula mucilaginosa), A Shi Trichosporon cutaneum (Trichosporon asahii), trichosporon cutaneum (Trichosporon Cutaneum), prepared Chinese ink trichosporon cutaneum (Trichosporon inkin), viscosity trichosporon cutaneum (Trichosporon mucoides), absidia corymbifera (Absidia corymbifera), pod membrane A Ye Sieve bacterium (Ajellomyces capsulatus), dermatitis A Yeluo bacterium (Ajellomyces dermatitidis), Benzene is deceived minor details skin bacterium (Arthroderma benhamiae), Arthroderma fulvum (Arthroderma Fulvum), Arthroderma gypseum (Arthroderma gypseum), Arthroderma incurvatum (Arthroderma incurvatum), Arthroderma otae (Arthroderma otae), Fan Buruixi Mi Jiepi bacterium (Arthroderma vanbreuseghemii), aspergillus flavus (Aspergillus flavus), Aspergillus fumigatus (Aspergillus fumigatus), aspergillus niger (Aspergillus niger), Blastomyces dermatitidis (Blastomyces dermatitidis), Ka Shi branch spore Saksenaea vasiformis (Cladophialophora carrionii), Posadasis spheriforme (Coccidioides immitis), cotton-shaped wheat psoriasis (Epidermophyton Floccosum), Exophiala dermatitides (Exophiala dermatitidis), Fonsecaea pedrosoi (Fonsecaea Pedrosoi), Fusarinm solani (Fusarium solani), Histoplasma capsulatum (Histoplasma Capsulatum), Du Shi histoplasma capsulatum (Histoplasma duboisii), Horaea werneckii (Hortaea werneckii), (Madurella grisae), microsporum canis (Microsporum Canis), microsporum fulvum (Microsporum fulvum), Microsporum gypseum (Microsporum gypseum), volume branch Mucor (Mucor circinelloides), the red shell of red sphere bundle (Nectria haematococca), paecilomyces varioti (Paecilomyces variotii), Brazilian secondary ball Pityrosporion ovale (Paracoccidioides brasiliensis), Penicillium marneffei (Penicillium Marneffei), the swollen bacterium (Pseudallescheria boydii) of Podbielniak foot, Rhizopus arrhizus (Rhizopus Arrhizus), Rhizopus oryzae (Rhizopus oryzae), Rhizomucor pusillus (Rhizomucor pusillus), Most advanced and sophisticated match many spores (Scedosporium apiospermum), schizophyllum commune (Schizophyllum Commune), Sporothrix schenckii (Sporothrix schenckii), alpha fungus (Trichophyton mentagrophytes), Trichophyton rubrum (Trichophyton rubrum) and wart Shape trichophyta (Trichophyton verrucosum).
Protozoan
[0262] protozoan is zooid protist, and major part is single celled activity The property protist, it is taken food by phagocytosis, but a large amount of exceptions are also arranged. Protozoan spreads all over In water environment and soil, usually survive at dry period as sporangiocyst or spore. Protozoan one As exist with two kinds of citation forms: movable growth type is called " trophosome "; With static Anti-type is called sporangiocyst (although some protozoan of causing a disease has much complicated life cycle). Vegetative form is bred in tissue, causes the damage of clinical disease. Sporangiocyst is environment externally Middle survival, the form of normally being propagated to the host by the host.
[0263] some protozoan experiences the interstage in hematophagus. For example, Bu Shi Trypanosome (Trypanosoma brucei) causes that in ox African typanosomiasis nagana (lethargus) and that add That disease. Trypanosoma bocagei (T.brucei) has complicated life cycle, by the tsetse fly carrier that bites Propagate in the mammal of existence. The dried blood because the tsetse fly that infects is taken food is so it is with the Asia The circulation trypomastigote is expelled in host's blood flow. In host's blood flow, metacyclic trypomastigote turns to Turn to the blood flow trypomastigote, they are bred in host body fluids (blood, lymph and spinal fluid), Change the mechanism by antigen and to have avoided immune system attack. By infection host the adopting of dried blood of taking food Fly picked-up blood flow trypomastigote. In the tsetse fly alimentary canal, before being divided into, the blood flow trypomastigote follows The ring trypomastigote. Finally, front circulation trypomastigote is divided into metacyclic cone whip in the insect glandula The hair body, the end lives cycle.
[0264] based on transfer method, many protozoans are classified as 4 groups: rhizopodea, Infusoria, Flagellata and sporozoa.
[0265] rhizopodea is commonly referred to amoeba, by extending (the vacation of their cytoplasm part Foot) mobile. They are usually located in seawater and the fresh water. Entamoeba histolytica (Entamoeba Histolytica) cause amcbiasis. Entamoeba histolytica (E.histolytica) is with chronic tired Labor syndrome associates.
[0266] Infusoria (Ciliophora or Ciliates) is by using a plurality of ciliums to move. Balantidium Coli (Balantidium coli) can the infected person enteron aisle, and it can be attacked there With destruction intestines lining. Its normal habitat is the pork pig enteron aisle, but that it also may reside in is global In seawater and the fresh water, cause the disease that is called balantidiasis.
[0267] Flagellata (Flagellates) is have one or more flagellums former lively The thing subphylum. This group member causes following disease: trichomoniasis, giardiasis, trypanosomiasis And leishmaniasis.
[0268] sporozoa (typically being inactive) is that a class parasitic protozoal is moving Thing comprises plasmodium and toxoplasm, causes respectively malaria and toxoplasmosis. They had both had and had had The property phase, have vegetative phase again. Their main target intestinal epithelial cells, but also may reside in In liver and other organ.
[0269] the invention provides by giving the protozoan adenylyl ring of patient treatment amount Change method and the medicine of the disease that the prevention of enzyme conditioning agent and treatment patient cause by protozoal infections Compositions, wherein said protozoan is selected from following order: Gregarinia, Coccidia, blood spore Sub-worm order and Piroplasmida.
[0270] the invention provides by giving the protozoan adenylyl ring of patient treatment amount Change method and the medicine of the disease that the prevention of enzyme conditioning agent and treatment patient cause by protozoal infections Compositions, wherein said protozoan is selected from: Acanthamoeba castellanii (Acanthamoeba Castellanii), two bud babesias (Babesia bigemina), babesia canis (Babesia canis), It is little to separate babesia (Babesia divergens), vole babesia (Babesia microti), colon Bag infusorian (Balantidium coli), Bei Shi shellfish promise sporozoite (Besnoitia besnoiti), small Cryptosporidium (Cryptosporidium parvum), circle spore coccidia (Cyclospora Cayetensis), eimeria tenella (Eimeria acervulina), ox eimeria tenella (Eimeria Bovis), Bu Shi eimeria tenella (Eimeria brunetti), carp eimeria tenella (Eimeria Carpelli), (Eimeria cyprinorum), nothing left body eimeria tenella (Eimeria irresidua), Large-scale eimeria tenella (Eimeria magna), huge eimeria tenella (Eimeria maxima), Gentle eimeria tenella (Eimeria mitis), poison eimeria tenella (Eimeria necatrix), Ni Shuerci eimeria tenella (Eimeria nieschulzi), perforation eimeria tenella (Eimeria Perforans), method is thought eimeria tenella (Eimeria phasiani), precocious eimeria tenella (Eimeria praecox), liver eimeria tenella (Eimeria stiedae), Eimeria Tenella (Eimeria tenella), cut shape eimeria tenella (Eimeria truncata), (Eimeria zurmii), Entamoeba histolytica (Entamoeba histolytica), Lan Shi giardia lamblia (Giardia Lamblia), Leishmania donovani (Leishmania donovani), microsporidian (Microsporidia), Fu Shi Na Geli amoeba (Naeglaria flowleri), plasmodium falciparum (Plasmodium falciparum), malariae (Plasmodium malariae), ovale malaria Protozoon (Plasmodium ovale), Plasmodium vivax (Plasmodium vivax), Ka Shi lung spore Worm (Pneumocystis carinii), neuron sarcocystis (Sarcocystis neurona), mutton Sporozoite (Sarcocystis tenella), toxoplasma gondii (Toxoplasma gondii), vagina hair Trichomonad (Trichomonas vaginalis), trypanosoma bocagei (Trypanosoma brucei) and Ke Shi cone Worm (Trypanosoma cruzi).
Metazoa
[0271] the metazoa pathogen comprises tapeworms, Trematoda and Nemata. Tapeworms Be a guiding principle in the flat worms door, comprise the parasitics that is called tapeworm (cestode or tapeworm) Flatworm, it is lived in the vertebrate alimentary canal as adult, and often gives birth to as the young Live in the body of many animals. The Cyclophyllidea tapeworm is wherein most important people and performing animal The tapeworm parasitic animal and plant. The Cyclophyllidea tapeworm comprises the diphlidium caninum (Dipylidium that is carried by flea And infect the human owner of pet (such as dog and cat) and pet caninum); Diplacanthus nanus (Hymenolepis nana), it infects mammal, comprises the people, and is carried by beetle; Dwindle Hymenolepis (Hymenolepis diminuta), it uses insect to feed as the intermediate host infection The breast animal; And armed tapeworm's taeniasis suis (Taenia solium) and teniarhynchosis taeniarhynchus saginatus (T. Saginata). Other tapeworm of causing a disease comprises the fish tapeworm for tapeworm the longest among the people (Diphyllobothrium latum) and cause the Echinococcus granulosus of hydatid cyst disease (Echniococcus granulosis).
[0272] Trematoda (Trematodes) is a guiding principle in the flat worms door. Fluke (Trematodes) be the parasitics flatworm that is commonly referred to fluke (fluke). Fluke can be based on them The genealogical classification of infecting is two groups. Organizing fluke is the species that infect bile duct, lung or other tissue. This group comprises lung fluke Paragonismus westermani (Paragonimus westermani), and liver inhales Worm clonorchis sinensis (Clonorchis sinensis) and Fasciola hepatica (Fasciola hepatica). Another Group is called blood fluke, and its some stage in their life cycle is settled in the blood. Blood is inhaled Worm comprises a plurality of Schistosoma species that cause snail fever.
[0273] Nemata is the roundworm that comprises many parasitics forms, comprises majority of plant With the pathogen in the animal. The nematode that colonizes among the people comprises whipworm (Tichuris), duodenum Worm (hookworm and Necator), pinworm (Enterobius), nematode (Strongyloides), roundworm and blood Filaria. The nematodes pathogen comprises Wuchereria, filaria volvulus, Loa loa, imperial nematode (Guinea worm) and bow roundworm. Trichina (Trichinella spiralis) species are commonly referred to and revolve Caterpillar (trichina worm) is present among rat, pig and the people, causes trichinosis. The shellfish roundworm (Baylisascaris) usually parasitize in the wild animal, but it also can be fatal to the people. Twist with the fingers Turning to haemonchus (Haemonchus contortus) is one of infectant the abundantest in the sheep.
[0274] on the one hand, the present invention enters pathogenic disease states or logical by the prevention pathogen infection Cross and make pathogen infection be returned to non-pathogenic disease states by pathogenic disease states, thus prevention or treatment eucaryon Pathogenic infection. Pathogenic disease states comprises any favourable or help to pathogen when entering the host In the state that infects, comprise that the gene expression relevant with morbidity and/or albumen produce and with pathogenic The change that state is relevant for example changes shape or form, formation mycelia, increase or reduces growth Speed, germination, excystation, release toxin, expression virulence factor, formation pod membrane and formation are biological Film. Pathogenic disease states also comprises expresses the gene relevant with morbidity, for example provides mechanism to escape the place Main immune system, remove nutrients, change activity, injure host tissue and be distributed to whole Gene in host cell, tissue and the organ.
[0275] the infectious eukaryotic pathogens of prevention enters pathogenic disease states or pathogen is returned Be that non-pathogenic disease states can produce beneficial effect to prevention and treatment pathogenic infection again, comprise subtracting Light or prevention infection symptoms, increase the invasion and attack pathogen to the sensitiveness of host immune system, slow down Pathogenic growth, prevention sporogenesis, pre-Ozoban produce, the prevention virulence factor is expressed, with And make pathogen reacting with the inconsistent mode of host environment, and its infection host of reverse influence Ability.
[0276] in certain embodiments, the adenylyl cyclase of eucaryote pathogen is pH/HCO3/CO 2Responsive type. The adenylyl cyclase of eucaryote pathogen can be solubility Adenylyl cyclase (sAC) perhaps can have remarkable homology with sAC.
[0277] regulate the eukaryotic pathogens adenylyl cyclase comprise suppress cyclase activity or The activation cyclase activity. Suppress the cellular level that adenylyl cyclase will weaken cAMP, simultaneously The activation of adenylyl cyclase will increase cell cAMP level.
[0278] eukaryotic pathogens adenylyl cyclase conditioning agent can have biocidal effect Or Biostatic effect. Biostatic refers to basically limit the effect of pathogenic growth ability, Basically can lethal pathogens and kill livestock the thing treatment. Yet conditioning agent may not effectively kill cause of disease Body.
[0279] in one embodiment, the present invention has characterized inhibition eukaryotic pathogens adenosine The method of acyl cyclase, described method comprise makes eukaryotic contact inhibition eukaryotic pathogens adenosine The compound of acyl cyclase.
[0280] in one embodiment, the present invention has characterized treatment by the cause of disease among the patient The method that the eukaryotic pathogens of body adenylyl cyclase mediation infects, described method comprise regulates disease The adenylyl cyclase of substance.
[0281] in order to treat the patient, the conditioning agent of preferred eukaryotic pathogens adenylyl cyclase Can significantly not suppress or activate patient's adenylyl cyclase (or guanylate cyclase). With respect to Patient's adenylyl cyclase has enough optionally, and conditioning agent helps to guarantee to realize sense The catch an illness therapeutic action of substance is done and patient's adenylyl cyclase is not produced unfavorable adjusting With.
[0282] term used herein " patient " need with method of the present invention and group to refer to Any biology of compound treatment perhaps needs to adopt method and composition of the present invention to prevent Any biology that the property treatment is protected from infection. Described patient can be plant or animal. Described trouble The person animal comprises fish, bird or mammal. Described patient can be domestic animal, for example ox, pig, Sheep, poultry and horse perhaps can be pet, for example dog and cat. Described patient can also for The people.
[0283] method of the present invention and pharmaceutical composition can also be used for the treatment of or be in advance windproof Danger patient's infection, for example infection of prevention or treatment hand postoperative patient.
[0284] human patients can for other side health the people, perhaps can be to suffer from To the pathogenic infection especially people of responsive illness. For example, described people can be for owing to infect HIV, because Chemotherapy, because suffer from leukemia, because immunosuppressive drug or because opium Class medicine and the people of immune function depression. Described people transplants recipient or bright the wounded.
[0285] eukaryotic pathogens adenylyl cyclase conditioning agent can include but not limited to little Molecule, fit, siRNA.
[0286] in one aspect of the invention, eukaryotic pathogens adenylyl cyclase conditioning agent can Think fitly, it is few nucleic acid or peptide molecule in conjunction with certain target molecules. They can be clear and definite Be synthesized, perhaps can use multiple screening technique known in the art such as yeast two-hybrid to be System is by selecting in the mixture.
[0287] in one aspect of the invention, eukaryotic pathogens adenylyl cyclase conditioning agent can Think little molecule. In this article, the little molecule of term refers to little organic compound, for example heterocycle, Peptide, sugar, steroids etc. Small-molecule modulators preferably have be lower than about 1500 dalton, More preferably less than about 500 daltonian molecular weight. Described compound can be modified, to strengthen effect Power, stability, drug compatibility etc. Can be by synthetic or natural library of compounds screening Candidate's conditioning agent compound. The synthetic compound library can be purchased by numerous companies, comprises Maybridge Chemical Co. (Trevillet, Cornwall, UK), Comgenex (Princeton, N.J.), Brandon Associates (Merrimack, N.H.) and Microsource (New Milford, Conn.). Combinatorial libraries is obtainable, perhaps can be according to known synthetic technology Preparation. Perhaps, the native compound library of bacterium, fungi, plant and animal form of extract Can derive from for example Pan Laboratories (Bothell, Wash.) or MycoSearch (NC), or The person is easy to by method production well-known in the art. In addition, can be by conventional chemistry Further modify library and the compound of natural and synthetic generation with Measurement for Biochemistry.
[0288] small-molecule modulators of eukaryotic pathogens adenylyl cyclase includes but not limited to be combined with cyclase ATP territory, CO2/HCO 3 -The responsive territory of/pH or other are regulated albumen The interactional little molecule of binding site. Can use high-throughout biochemical mensuration, enzyme Type is measured or cellular type is measured the inhibition activity of screening Small molecular libraries. Configurable described mensuration, Formed the ability of cAMP by ATP to detect test compounds inhibition or activation.
[0289] in certain embodiments, can be by catechol estrogen and derivative choosing thereof Select the small-molecule modulators of eukaryotic pathogens adenylyl cyclase. Catechol estrogen is steroids Metabolin is by in conjunction with various kinds of cell target activation physiological reaction. Catechol estrogen can be direct Suppress the solubility adenylyl cyclase and stride the film adenylyl cyclase. The catechol estrogen derivative Comprise that the functional group on the estrogen core wherein modified the change of (for example by reduction or oxidation) Compound, the perhaps metabolin of catechol estrogen. Catechol estrogen can be by further derivation, For example derivation is ester, ether, oxime, hydrazone, azanol, carbamate, alkoxy ester, carbonic ester Or PEG derivative.
[0290] in other embodiments of the present invention, small-molecule modulators is selected from WO Disclosed compound in 2005/070419, this patent by reference integral body is attached to herein. In other embodiments, eukaryotic pathogens adenylyl cyclase conditioning agent is selected from row in table 1 The compound that goes out and combination thereof.
[0291] the present invention also provides prevention or treatment patient to be caused by the eukaryotic pathogens infection The method of disease, the method gives the patient and contains the eukaryotic pathogens adenylyl for the treatment of effective dose The composition of cyclase conditioning agent and pharmaceutically acceptable excipient.
[0292] on the other hand, the invention provides pharmaceutically acceptable composition, it contains One or more aforesaid eukaryotic pathogens adenylyl cyclases for the treatment of effective dose are regulated Agent, described conditioning agent and one or more pharmaceutically acceptable excipient are formulated together. Live Property composition and excipient can be mixed with composition and formulation according to methods known in the art. As Hereinafter describe in detail, pharmaceutical composition of the present invention can be mixed with especially with solid or liquid Form gives, and comprises being suitable for those following forms: (1) is oral to be given, for example tablet, capsule Agent, pulvis, granule, the paste that is applied to tongue, water-based or nonaqueous solution or suspendible Agent, gavage agent or syrup; (2) stomach and intestine give outward, for example by subcutaneous, intramuscular or intravenous Injection is for example as sterile solution or suspension; (3) local application is for example as being applied to skin The creme of skin, lung or mucous membrane, paste or spray; Or in (4) vagina or in the rectum, for example do Be pessary, creme or foaming agent; (5) hypogloeeis or cheek clothes; (6) eye clothes; (7) transdermal; Or (8) The nose clothes.
[0293] pharmaceutical composition for the treatment of effective dose of the present invention be enough to the treatment or the prevention by Eukaryotic pathogens infects the disease that causes. The treatment effective dose can prevent pathogen infection to become to cause Diseased state significantly suppresses the virulence factor relevant with pathogenic disease states, and/or makes pathogen by causing a disease Replying state is non-pathogenic disease states. The dosage of active component can be according to using reason and individual suffering from Person and becoming. Dosage can be based on age of weight in patients, patient and health condition and to compound Or the tolerance of composition and adjusting.
[0294] term " pharmaceutically acceptable " is used in reference to those rational doctor at this paper Learn be applicable in the determination range those compounds of contacting with patient tissue, material, composition and / or formulation, tool with regard to its toxicity, excitant, allergy or other problem or concurrent factor Rational interests/risk ratio is arranged.
[0295] phrase used herein " pharmaceutically acceptable excipient " refers to pharmaceutically Acceptable material, composition or solvent, for example liquid or solid filler, diluent, carry Body, produce assistant (for example lubricant, talcum powder, dolomol, calcium stearate or stearic acid Zinc or stearic acid), solvent or capsule formed material, they relate to carries or transports therapeutic compound, Be used for giving the patient. Compatible with other composition of preparation and to the patient on the harmless meaning, every Planting excipient all should be " acceptable ". Some can be used as pharmaceutically acceptable excipient The example of material comprise: sugar, for example lactose, dextrose plus saccharose; Starch, for example corn Starch and farina; Cellulose and derivative thereof, for example sodium carboxymethylcellulose, ethyl Cellulose and cellulose acetate; Gelatin; Talcum powder; Wax; Oils, for example peanut oil, cottonseed Oil, safflower oil, sesame oil, olive oil, corn oil and soya-bean oil; Glycol, for example ethylene glycol and Propane diols; Polyalcohol, for example glycerine, sorbierite, sweet mellow wine and polyethylene glycol; Ester, for example Ethyl oleate and ethyl laurate; Agar; Buffer; Water; Isotonic saline solution; The pH buffering is molten Liquid; With other the nontoxic compatible material that is used for pharmaceutical preparation. If needed, can add certain A little sweeteners and/or flavor enhancement and/or colouring agent. Other suitable excipient is found in the standard medicine Learn textbook, for example see " Remington ' s Pharmaceutical Sciences ", The Science and Practice of Pharmacy, the 19th edition, Mack Publishing Company, Easton, Pa., (1995).
[0296] excipient joins in the composition for multiple purpose. Diluent increases solid The volume of pharmaceutical composition, and can prepare the group that contains that is easier to patient and medical personnel's operation The pharmaceutical dosage form of compound. The diluent of solid composite comprises that for example microcrystalline cellulose (for example Avicel
Figure A20088000833900971
), micro mist cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, glucose, Bibasic Calcium Phosphate dihydrate, three alkali calcium phosphates, kaolin, magnesium carbonate, magnesia, maltodextrin, sweet mellow wine, polymethacrylates (Eudragit for example
Figure A20088000833900972
), potassium chloride, powdered cellulose, sodium chloride, sorbierite and cunning Stone flour.
[0297] solid composite medicament that is pressed into such as the formulation of tablet can comprise Such excipient: its function helps active component and other excipient after being included in compacting Combine. The bond that is used for solid composite medicament comprise gum arabic, alginic acid, Carbomer (for example carbopol), sodium carboxymethylcellulose, dextrin, ethyl cellulose, gelatin, Guar gum, hydrogenated vegetable oil, hydroxyethylcellulose, hydroxypropyl cellulose (Klucel for example
Figure A20088000833900973
), hydroxypropyl methylcellulose (Methocel for example
Figure A20088000833900974
), liquid glucose, Magnesiumaluminumsilicate, maltodextrin, methylcellulose, polymethacrylates, PVP (Kollidon for example
Figure A20088000833900981
、 Plasdone
Figure A20088000833900982
), pregelatinized starch, sodium alginate and starch.
[0298] rate of dissolution of solid composite medicament in Stomach in Patients of compacting can lead to Crossing to composition adding disintegrant increases. Disintegrant comprise alginic acid, calcium carboxymethylcellulose, Sodium carboxymethylcellulose (Ac-Di-Sol for example、Primellose
Figure A20088000833900984
), cataloid, Ac-Di-Sol, PVPP (Kollidon for example
Figure A20088000833900985
、Polyplasdone
Figure A20088000833900986
), guar gum, Magnesiumaluminumsilicate, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycollate (Explotab for example
Figure A20088000833900987
) and starch.
[0299] can add glidant, with flowing of the solid composite that improves non-compacting Property, and improve the accuracy of administration. Can comprise the colloid titanium dioxide as the excipient of glidant Silicon, magnesium trisilicate, powdered cellulose, starch, talcum powder and three alkali calcium phosphates.
[0300] when the formulation by pressed powder composition preparation such as tablet, by punching Head is exerted pressure to composition, and dyeing. Some excipient and active component have the punching of adhering to The trend of head surface and dyestuff, this can make product form indenture and other surface imperfection. Can To add lubricant to composition, adhere to and be easy to by the dyestuff releasing product to reduce. Lubricant Comprise dolomol, calcium stearate, glyceryl monostearate, palmitic acid tristerin, Rilanit special, hydrogenated vegetable oil, mineral oil, polyethylene glycol, Sodium Benzoate, dodecyl Sodium sulphate, stearoyl fumaric acid sodium, stearic acid, talcum powder and zinc stearate.
[0301] in composition of liquid medicine of the present invention, with eukaryotic pathogens adenylyl ring Change enzyme conditioning agent and any other solid excipient and be dissolved or suspended in the liquid-carrier described liquid The body carrier is water, water for injection, vegetable oil, alcohols, polyethylene glycol, propane diols or glycerine for example.
[0302] composition of liquid medicine can comprise emulsifying agent, with will be in liquid-carrier not Molten active component or other excipient are distributed in the whole composition equably. Can be used for this The emulsifying agent of bright fluid composition for example comprise gelatin, yolk, casein, cholesterol, Ah Draw uncle's natural gum, tragacanth, Irish moss, pectin, methylcellulose, carbomer, 18 Pure and mild cetanol.
[0303] composition of liquid medicine of the present invention can also comprise thickener, produces to improve The mouthfeel of thing and/or coated GI lining. Such material comprises gum arabic, marine alga Acid, bentonite, carbomer, calcium carboxymethylcellulose or sodium, 18 hexadecanols, methyl fiber Element, ethyl cellulose, gelatin, guar gum, hydroxyethylcellulose, hydroxypropyl cellulose, Hydroxypropyl methylcellulose, maltodextrin, polyvinyl alcohol, PVP, propylene carbonate, Propylene glycol alginate, sodium alginate, sodium starch glycollate, bassora gum starch and xanthans.
[0304] can add sweetener, for example sorbierite, asccharin, saccharin sodium, sucrose, Aspartame, fructose, sweet mellow wine and invert sugar are to improve taste. Flavor enhancement and flavoring agent can Make formulation better to eat for the patient. Can be included in the medicine that is usually used in the present composition Flavor enhancement and flavoring agent comprise maltol, vanillic aldehyde, Ethyl vanillin, menthol, citric acid, Fumaric acid, ethyl maltol and tartaric acid.
[0305] can add anticorrisive agent and chelating agent by the level of taking in safety, for example alcohols, Sodium Benzoate, butylated hydroxytolyene, Butylated Hydroxyanisole and ethylenediamine tetra-acetic acid are to improve stable storing The property.
[0306] according to the present invention, fluid composition can also comprise buffer, for example grape Saccharic acid, lactic acid, citric acid or acetic acid, gluconic acid sodium salt (sodium guconate), sodium lactate, Natrium citricum or sodium acetate. Formulation science worker is based on experience and consider standard method and this The reference works in field is determined the selection of excipient and used amount easily.
[0307] can also use any pharmaceutically acceptable colouring agent dyed solid and liquid The body composition is with the outward appearance of improving them and/or be beneficial to patient's identification product and the unit dose water gaging Flat.
[0308] formulation of the present invention can be for containing the capsule of composition, for example, and firmly Powdered or granular solid composite of the present invention in shell or the soft shell. Described shell can be by gelatin Preparation and randomly comprises plasticizer, for example glycerine and sorbierite, and comprise opacifier or Toner.
[0309] composition for tablet or capsule-filling can prepare by wet granulation. In wet granulation, active component and the excipient of mixing portion or whole powder types, then Further mix in the presence of liquid, described liquid is generally water, and it makes powder agglomates become particle. Screening and/or abrasive grains, a required degree is screened and/or be ground to drying then. Then With the particle film-making, perhaps can before film-making, add other excipient, for example glidant and/or lubricated Agent.
[0310] the film-making composition can be by being dry mixed conventional preparation. For example, can be with active component Be pressed into dummy slider or thin slice with the blend compositions of excipient, be ground into then compacted granules. Press Real particle can be pressed subsequently in flakes.
[0311] as to the substituting of dry granulation, can use direct compress technique with the mixing group Divide direct pressing to become the compacting formulation. Directly compression produces the more agranular tablet of homogeneous. Especially The excipient that is suitable for the direct pressing film-making comprises microcrystalline cellulose, spray-dired lactose, phosphorus Acid two calcium dihydrates and colloidal silica. These excipient and other excipient are at direct pressing Correct use in the tablet be this area those direct pressing concrete preparation aspect in blocks is had The personnel of experience and technology are known.
[0312] the capsule-filling agent can comprise any aforementioned mixture of describing about film-making And particle, still, they do not carry out last film-making step.
[0313] composition of the present invention can give separately, perhaps can make up a kind of or many Planting other therapeutic agent (for example antibiotic) gives. Antibiotic can include but not limited to macrolide (erythromycin (eryrthromycin), azithromycin (azithromaycin), CLA etc.), Beta-lactam (penems, cephalosporanic olefinic, Carbapenems and carbacephems, for example mould Element, Amoxicillin, Ticarcillin, cephazoline, cephalo chlorine, Cefepime, ceftriaxone, Loracarbef, Imipenem etc.), aminoglycoside (gentamicin, tobramycin etc.), glycopeptide (ten thousand Ancient mycin etc.), quinolone (Ciprofloxacin, lavo-ofloxacin, Ofloxacin etc.), tetracycline (four The), oxazolidone (Linezolid etc.) such as ring element, fortimicin but, woods amine (lindamycin etc.) And chloramphenicol.
[0314] composition of the present invention can make up one or more antifungal agents and gives. This The antifungal agent of sample can include but not limited to that allylamine and other non-azoles ergosterol biology close Become inhibitor (Amorolfine, Butenafine, Naftifine, spy must naphthalene sweet smell etc.); Antimetabolite (fluorine Cytimidine etc.); Azoles (Fluconazole, Itraconazole, first ketoconazole, posaconazole, voriconazole, Clotrimazole, econazole, Miconazole, Oxiconazole, sulconazole, terconazole, tioconazole etc.); Glucan synthetic inhibitor (Caspofungin etc.); And polyenoid (amphotericin B, nystatin, Horse rhzomorph etc.).
[0315] composition of the present invention can make up one or more antiparasitics and gives, Described antiparasitic include but not limited to diloxanide, Eflornithine, furazolidone, she Dimension rhzomorph, levamisol, melarsoprol, atabrine, metronidazole, Ornidazole, paromomycin, Pentylenetetrazol, piperazine, pyrimethamine, Pentostam, sulfadoxine and Tinidazole.
[0316] in therapeutic alliance, the conditioning agent of eukaryotic pathogens adenylyl cyclase can With another kind of medicament (for example antibiotic formulations) with and any combination begin treatment before, in the middle of Or give afterwards, namely before the other treatment of beginning and central, before and afterwards, work as neutralization After neutralization, give afterwards or before.
[0317] in one embodiment of the invention, can be with the eukaryotic pathogens adenylyl The cyclase conditioning agent adds animal feed, is used for preventing and/or treating the disease of domestic animal and pet. This can followingly realize: the premixing feedstuff that preparation is suitable, it contains the eukaryotic pathogens gland of effective dose Glycosides acyl cyclase conditioning agent, and premixing feedstuff mixed completely decide in the grain. Perhaps, can will contain There are intermediate concentrate or the feed additive of active component to be mixed in the feed. Can prepare and Give such premixing feedstuff and complete mode of deciding grain below with reference to document (for example is described in " Applied Animal Nutrition ", W.H.Freedman and CO., San Francisco, U.S.A., 1969 or " Livestock Feeds and Feeding " O and B books, Corvallis, Ore., U.S.A., 1977).
[0318] another aspect of the present invention is the method in external evoked pathogenic disease states. By Make eukaryotic pathogens contact the activator of one or more adenylyl cyclases, can lure external Lead the change relevant with pathogenic disease states, comprising: increase growth rate, under multiple condition (for example The CO that increases2Level) growth, form change and the gene relevant with pathogenic disease states and albumen Express. In addition, induce pathogenic disease states can then test subsequently candidate compound and suppress pathogenic disease states Or the ability of some aspect of pathogenic disease states.
[0319] is used for analyzing the effect of pathogen being changed or keeping the ability of pathogenic disease states Model system can be system in vitro system or the body. For example, can be two kinds of in vitro culture The trypanosoma bocagei of form (T.brucei): blood flow trypomastigote and front circulation trypomastigote. In vivo With external, the high-cell density of blood flow type cell all triggers by strip and breaks up to stubby shape. Should Although differentiation by be called short and thick inducible factor (Stumpy Inducing Factor) (SIF) not by really Fixed density induction factor control, but cause cell cycle arrest (Vassella through the cAMP approach Deng, J.Cell Science.1997 November; 110 (21 chapter) 2661-71 page or leaf). Therefore, cAMP Approach develops by Cycle Regulation, and can infect as control trypanosoma bocagei (T.brucei) Good candidate.
[0320] recent decades, the laboratory mouse has been often to carry out being difficult to of wherein studying The pathogenic infection disease research of rule laboratory operation provides alternative platform. For example, separate 4 kinds of rodent malaria (Plasmodium yoelii (Plasmodium from African wild bush clump rat Yoelii), Bai Shi plasmodium (Plasmodium berghei), Xia Shi plasmodium (Plasmodium Chabaudi) and Fen Shi plasmodium (Plasmodium vinckei)) be suitable at the laboratory grinding tooth Growth (Carter, R.﹠Diggs, C.L.Parasitic Protozoa.359-465 page or leaf in the animal. Academic Press, New York/San Francisco/London, 1977).
[0321] be used in the body of metazoa pathogen and external model also be this area Know. For example, in tapeworm worm research, broad research the Hymenolepis species and in Grow hole tapeworm species, because their life cycle may be easy in vitro culture, and can With in the laboratory animal host, keep expediently (about the summary of tapeworm model, referring to Siles-Lucas, M.﹠Hemphill, A., Adv Parasitology.2002.51 volume, 133-230 Page or leaf).
[0322] can finish the evaluation eucaryon by the mensuration that detects the adenylyl cyclase activity The conditioning agent of pathogen adenylyl cyclase. May be implemented in a variety of ways the detection adenylyl cyclase Activity comprises the formation that detects cAMP, and detects ATP to the transformation of cAMP. This A little technology are well known in the art, and contain the commercially available available kit of detailed protocol also It is a selection. For example, the commercial reagent box comprises the cAMP that derives from Applied Biosystems Chemiluminescence immunoassay kit cAMP-Screen DirectTM, derive from the cAMP Radiometric FlashPlate of PerkinElmer( 125I) measure kit, derive from Sigma-Aldrich CAMP enzyme immunoassay (EIA) kit, derive from the CatchPoint of Molecular Devices CAMP measures kit and derives from the cAMP colorimetric estimation kit of Calbiochem, at this Only lift several examples. Many commercially available available kits are estimated or are suitable for the cyclisation of high flux screening adenylyl Enzymatic activity.
[0323] concentration of cAMP can be measured detection by receptors bind in the sample (Nordstedt, C. and Fredholm, BB.Anal Biochem 189 volumes, 231-234 page or leaf. 1990). The cAMP that the method utilization exists in sample or standard items and radiolabeled Between the cAMP competition in conjunction with cAMP in conjunction with the albumen (accent of mammalian proteins kinases A for example The CRP albumen of joint subunit or Escherichia coli (E.coli)). Many diverse ways can be used for separating In conjunction with cAMP and free cAMP (such as filtration, precipitation etc.). Can use scinticounting Device detects the amount in conjunction with the protein-bonded radiolabeled cAMP of cAMP.
[0324] the another kind of method that detects cAMP concentration in the cell extract is by radiation Immunoassays, it utilizes cAMP specific antibody (Steiner etc., PNAS.64 volume, 367-373 Page or leaf, 1969). The modification method utilization of the method is for the single succinyl adenosine 3 ', 5 ' of 2 '-O--ring is single The specific antibody that phosphoric acid produces, for detection of the cAMP that flies mole (Harper etc., Journal of Cyclic Nucleotide Research. the 1st volume, 207-218 page or leaf .1975). Logical Cross and change cAMP into the higher affinity binding antibody acetyl derivatives, strengthen these The sensitivity of measuring. In this radiommunoassay, radiolabeled cAMP and sample or CAMP competition in the standard items is in conjunction with the cAMP-specific antibody. The radioactivity mark that separates combination The cAMP of note, and detect with scintillation counter. Although immunoassays are subjected to than aforesaid radioactivity Body method is sensitiveer, but it often needs more sample operation, and these operations may increase change The opposite sex and minute.
[0325] detection of adenylyl cyclase activity also may relate to quantitative ATP to cAMP Transformation. A kind of method utilization [32P]-ATP of mark, its by adenylyl cyclase be converted into [32P] cAMP. Another kind method comprise with cell with [3H] the adenine incubation, with mark ATP Born of the same parents in mixture. By adenylyl cyclase will [3H] ATP change into [3H] cAMP. Therefore, Will [3H] accumulation of cAMP is as the measurement standard of adenylyl cyclase activity. These two kinds of methods All need radiolabeled cAMP is separated with other component of reactant mixture, this is frequent Finish by carrying out sequential chromatography at Dowex cation exchange column and alumina column (Solomon etc., Analyical Biochemistry.58 volume, 541-548 page or leaf, 1974). Available In the another kind of method of measuring the adenylyl cyclase activity comprise use anti--cAMP antibody (above Described), to form at cell lysate and ATP incubation post-evaluation cAMP. The method is avoided The use radioactive substrates, and can be used for estimate the cAMP accumulation of intact cell. The significant consideration of this mensuration is that only small part ATP substrate changes cAMP into. Therefore, have The component of possible reactant mixture can disturb antibody-cAMP to interact. For this reason, must be to contain There is the solution of known cAMP concentration to confirm that the buffer that is used for the cAMP generation does not disturb cAMP Detect.
What [0326] it is important to point out that is, the adenylyl cyclase activity can be subjected to several factors Impact, this depend on the type (stride film or soluble) of adenylyl cyclase and its from Biological. The adenylyl cyclase activity depends on the situation that exists of bivalent cation, and/or depends on Other molecule have a situation, the carbon that described other molecule for example must exist in the incubation process The acid hydrogen salt. In addition, (it is by G albumen idol to stride the film adenylyl cyclase the detection mammal The connection acceptor is regulated by hormone) time, GTP (or GTP analog of non-hydrolysable) should be included in In the incubation. In addition, by the enzyme that exists in the cell lysate (nucleotidase and hydrolase) degraded ATP Can cause the substrate disappearance. For preventing this problem, can be by creatine phosphate and creatine phosphate kinases (or phosphorus Acid (enol) pyruvic acid and pyruvate kinase) carry out temperature under existing in the ATP regenerating system that forms Educate. At last, the phosphodiesterase that exists in cell lysate can be hydrolyzed to cAMP AMP. Therefore, incubation comprises one or more CD-840s usually, to prevent CAMP decomposes.
[0327] can also by immunoassays determine adenylyl cyclase measure in ATP to The transformation of cAMP. In this was measured, antigen cAMP binding antibody was then with the of mark Two antibody are attached to antigen-antibody complex. Detect then the amount of the labelled antibody of combination. The party Method is measured with respect to above-mentioned transformation has several advantages, a large amount of because it does not need to use32P, and cAMP does not need to pass through column chromatography for separation.
[0328] for measuring the adjusting activity of compound, can be to full cell or cell lysate Implement these mensuration. For determining that compound is to the inhibition of eukaryotic pathogens adenylyl cyclase activity Effect, pathogen can promote the cAMP level (CO that for example promotes via the target cyclase2、 HCO 3 -The pH level of level or reduction), be with or without under the condition of target compound and cultivate, And the cAMP level of analysis reduction. For measuring the activation of eukaryotic pathogens cyclase, pathogen Can in the presence of target compound, grow, and analyze the cAMP level of its increase. For measuring To the inhibition activity of people (or other patient) adenylyl cyclase, the cAMP level can increased Incentive condition under cultivate suitable cell in the culture. For example, the sAC stimulus comprises high Portugal Grape sugar (in the β cell), neurotrophic factor and/or lead albumen (netrin) (in neuron), TNF (in neutrophil cell), and for tmAC, stimulus comprises Forskolin, or In a large amount of Gs coupling of the person hormone any. Measure the cAMP level that target compound reduces. Perhaps, the reduction check that can pass through the foundation level of observation cyclase activity suppresses active.
[0329] for measuring the stimulating activity to people (or other patient) adenylyl cyclase, training The suitable cell of supporting in the thing can be cultivated in the presence of described compound, and increases the cAMP of monitoring Level.
[0330] the alternative mensuration of check adenylyl cyclase conditioning agent can be used purifying The adenylyl cyclase prepared product carries out together with compound to be tested. The adenylyl of studying Cyclase can pass through various ways purifying known in the art, and for example immunoprecipitation, employing resist The column chromatography of body, and the purifying of the fusion of heterogenous expression, for example polyhistidine tag (the His-mark) adenylyl cyclase. Polyhistidine tag is through being usually used in affinity purification at the large intestine bar The recombinant protein of the polyhistidine tag of expressing in bacterium or other prokaryotic expression system. By Centrifugal collection bacterial cell, the cell precipitation of generation can be with detergent or enzyme (for example lysozyme) Cracking. Thick lysate passes the post that contains the immobilization nickel ion, and this post is in conjunction with connecting the adenylyl cyclisation The polyhistidine tag of enzyme. Use then the phosphate buffer washing resin, to remove not and cobalt ions Or the interactional albumen of nickel ion specificity. Detersive efficiency can change by adding the 20mM imidazoles Kind, usually use then 150-300mM imidazoles eluted protein. The purity of albumen and amount can be led to Cross SDS-PAGE and Western blotting evaluation.
[0331] can also use immunoaffinity chromatography purifying adenylyl cyclase protein. Method Comprise antibody and the column packing of specific binding adenylyl cyclase are fixed. Cell lysate is worn Cross this post, the described albumen of this post selective binding. Can be by changing pH or salinity wash-out institute State albumen.
[0332] activity with pathogen sAC purifying heterogenous expression is passed through at bicarbonate, MgCl2Exist lower mensuration to determine with ATP. For measuring compound to pathogen infection sAC Selective, can count screening with people (or other host) the sAC albumen of purifying. Also Can implement further to count in order to the full cell lysate that Forskolin stimulates screening-it should The activity that reflects tmAC.
[0333] compound to the eukaryotic pathogens adenylyl cyclase selectively by should The work that the effect that compound produces pathogen cAMP and this compound produce patient cAMP Definite with comparing. For example, high selectivity suppresses the eukaryotic pathogens adenylyl cyclase Compound will significantly stop under the following conditions the pathogen cyclase to produce cAMP: therein During this compound, this cyclase does not answer catalysis cAMP to form. In addition, alternative cpd To can significantly not suppress or stimulate patient's adenylyl cyclase.
[0334] one aspect of the present invention provides and identifies the eukaryotic pathogens adenylyl cyclase The method of selective modulator. Selectively can of eukaryotic pathogens adenylyl cyclase conditioning agent By inhibitory action or the spread effect of detection to the pathogen adenylyl cyclase, and detect To the adenylyl cyclase of target patient be used for determine. The conditioning agent of high selectivity is with shadow Ring the activity of pathogen adenylyl cyclase, but to the activity of the adenylyl cyclase of target patient To almost not have or not effect.
[0335] can animal model test eukaryotic pathogens adenylyl cyclase conditioning agent Render a service and potential side effect. Can by fixing organization being embedded section statining behind the paraffin, use afterwards Microscopic examination detects the effect of infecting tissue.
[0336] detailed description of the conventional method of this paper discussion is for example at analysis of protein, gene table Those methods that reach, use in the light microscope, Bacteria Culture, mammaliancellculture etc., Can derive from numerous publications, such as Molecular Cloning:A Laboratory Manual (Cold Spring Harbor Laboratory Press.1989), Current Protocols in Microbiology (Wiley InterScience), Current Protocols in Cell Biology (Wiley InterScience) and Current Protocols in Molecular Biology (Wiley InterScience). The equal integral body of all lists of references that this paper mentions is attached to this paper by reference In.
Embodiment
Embodiment 1.KH7 compound is to the effect of people's adenylyl cyclase
[0337] compound-base is selected from Chem Div library in their chemical structure.Measure these compounds, human soluble is striden the effect of film adenylyl cyclase to determine them.
Analyzed in vitro
[0338] the people sAC albumen with purifying is used for external adenylyl cyclase mensuration.This proteic purifying is specified in Litvin etc., 2003. (J.Biol.Chem.278:15922-15926.).This paper has also been described the general condition that the sAC cyclase is measured that is used for.The actual conditions that is used for external test is as follows.
[0339] for basic sAC activity, preparation is to the main mixture of mensuration that responds and all have sufficient volume, and it contains:
50mM?Tris(pH?7.5)
The 20mM creatine phosphoric acid
100U/ml creatine phosphoric acid kinases (CPK)
1mM?DTT
10mM?MgCl 2
[0340] the main mixture of equal portions is added to the people sAC of purifying.The KH compound of concentration shown in the mensuration mixture also comprises, or comprise isopyknic solvent (being DMSO) in contrast.Begin reaction by adding 5mM ATP (always measuring volume=100 μ L).Reaction mixture in 30 ℃ of incubations 30 minutes, is stopped by adding 100 μ l 0.2N HCl then.Stimulate condition determination to comprise with 40mM supercarbonate and 5mM CaCl 2Add to above main mixture.
[0341] in each sample, use the Correlate-EIA of Assay Designs directly to encircle the specification sheets detection ring AMP level of AMP mensuration test kit according to the manufacturer.
The cAMP accumulation is measured in the body
[0342] use DMEM (10%FBS, 1%L-glutamine, 1% penicillin/streptomycin) at 75cm 2Cultivate 293T cell or 4-4 cell (the hsACt stable transfection is gone among the 293T) in the tissue culture flasks, converge until approaching.Discharge cell with 3ml trypsinase by flask, then add 7ml DMEM, with in and trypsinase.Beat cell mixing by inhaling with 10ml serology transfer pipet.In the cell mixture of 3ml equal portions, add 6ml DMEM (pre-temperature is to 37 ℃), following afterwards thorough mixing: use the whole 9ml of reciprocating type pipettor sucking-off, and slowly ooze against wall of container.This mixes repetition 10 times, to guarantee the mixture homogeneous.Then 100 μ L cells are added in the 1.7ml Eppindorf pipe (Costar#3207) of each pre-silication, afterwards in 37 ℃ and 5%CO 2Middle incubation 60 minutes.This incubation carries out in the circle of 20 pipes is lived grooved rail (VWR#60986-100), and it can be transferred to water-bath fast with sample, and can mix several samples simultaneously.Behind incubation, add the DMSO solution (or only adding DMSO in contrast) of 1 μ L compound.Before adding compound and afterwards by of short duration (and slight) vortex mixed cell.Add compound, cell is in 37 ℃ of water-baths, afterwards in 37 ℃ and 5%CO 2Middle incubation 10 minutes.Behind this incubation, add 1 μ LIBMX or 1 μ L IBMX+ Buddhist SCH with reciprocating type pipettor.The 4-4 cell is accepted IBMX to final concentration 500 μ M IBMX.The 293T cell accepts IBMX and Buddhist SCH to final concentration is respectively 500 μ MIBMX and 10 μ M.IBMX mixture (for the 4-4 cell) and IBMX/FSK mixture (for the 293T cell) are 100X, and are dissolved among the DMSO.Cell mixing, and in 37 ℃ and 5%CO 2Middle incubation 15 minutes.By cell being placed ice bath stop measuring.By in 4 ℃ with centrifugal 7 minutes sedimentation cells of 2000x G.The sucking-off supernatant liquor adds 250 μ L 0.1N HCl to each cell precipitation, thorough afterwards vortex 1 minute.Be the room temperature incubation after 10 minutes, add every kind of sample of 30 μ L, and (Assay Designs, scheme Inc.#901-066) detects the cAMP level to be used for DirectCyclic AMP test kit to 70 μ L 0.1N HCl.This 30 μ L adds 70 μ L 0.1N HCl and formed the sample of describing in the step 5 of Assay Designs scheme.This sample should be in the setting-out line scope.
Figure A20088000833901091
Figure A20088000833901111
Figure A20088000833901121
Figure A20088000833901131
Figure A20088000833901151
Figure A20088000833901161
Figure A20088000833901171
Figure A20088000833901191
Figure A20088000833901201
Figure A20088000833901211
Figure A20088000833901231
Figure A20088000833901241
Figure A20088000833901251
Figure A20088000833901261
Figure A20088000833901271
Figure A20088000833901281
Figure A20088000833901291
Embodiment 2.
The KH7 compound is to the effect of trypanosoma bocagei (Trypanosoma brucei)
[0343] trypanosoma bocagei (T.brucei) has a plurality of adenylyl cyclase genes.Major part has similar topological framework: big variable extracellular region, single catalytic domain of striding film district and high conservative.Catalytic domain is Class IIId, with fungi adenylyl cyclase homology.Therefore we manage to determine that KH7, KH7.15 and KH7.14 are to trypanosoma bocagei (T.brucei) growth and the active effect of lysate.The structure of KH7, KH7.14 and KH7.15 is as follows:
Figure A20088000833901301
[0344] in 1 μ M to 300 μ M scope, cumulative KH7, KH7.15, the KH7.14 of concentration exists down, cultivates blood flow type cell and procyclic form cell.In DMSO, and (for blood flow type cell is HMI-9 directly to add growth medium with 1% DMSO final concentration with compound dissolution; For the procyclic form cell is SDM-79).Use Coulter counter monitoring cell density.In the blood flow type, the concentration of KH7 between 3-10 μ M effectively stops growth (referring to Fig. 1), and KH7.15 and KH7.14 only stop growth, supposition to be because pass through non-specific toxicity in the concentration that surpasses 100 μ M.The none test compounds has any effect to the growth of procyclic form.
[0345] use the full cell lysate of blood flow type to test these compounds to the active effect of lysate.In brief, ultrasonic (on ice) 5 * 10 in the lysis buffer of forming by 2mM Tris-HCl, 15mM KCl, 1mMEDTA, 1mM 2 mercapto ethanol, 100 μ M PMSF and 1 μ g/mL Trypsin inhibitor,Trasylol/leupeptin 6Individual cell.Use 20 μ L lysates/be determined at 15mM MgCl 2Carrying out adenylyl cyclase in 30 ℃ down with 50mM Tris-HCl pH value of solution=7.5 existence of 1mM ATP measures.KH7.14 and KH7.15 in any concentration to activity all less than effect, and 100 μ M KH7 the AC activity of full cell lysate moderate stimulation 1.5-2 doubly between (referring to Fig. 2).In external prevention blood flow type cell growth, this observations is consistent with the idea that the cAMP approach is controlled the cell cycle via the adenylyl cyclase activation for KH7.

Claims (438)

1. a treatment suffers from the method that is infected the patient of the disease that causes by eukaryotic pathogens, and described method comprises:
Give the eukaryotic pathogens adenylyl cyclase conditioning agent of described patient treatment amount.
2. the process of claim 1 wherein that the amount of the pathogenic agent adenylyl cyclase conditioning agent that given prevents significantly that effectively pathogenic agent from becoming pathogenic disease states by non-pathogenic disease states,
The amount of the pathogenic agent adenylyl cyclase conditioning agent that is perhaps wherein given makes pathogenic agent be replied basically by pathogenic disease states to be non-pathogenic disease states effectively.
3. the method for claim 2, the wherein said pathogenic agent adenylyl cyclase conditioning agent pathogenic agent that significantly prevents infections increases or reduces growth velocity.
4. the method for claim 2, wherein said pathogenic agent adenylyl cyclase conditioning agent reduces or significantly stops the expression of one or more virulence factors.
5. the process of claim 1 wherein that described pathogenic agent adenylyl cyclase conditioning agent suppresses the adenylyl cyclase of pathogenic agent.
6. the process of claim 1 wherein that described pathogenic agent adenylyl cyclase conditioning agent activates the adenylyl cyclase of pathogenic agent.
7. the process of claim 1 wherein that described pathogenic agent adenylyl cyclase conditioning agent has significant biocidal effect to pathogen infection.
8. the process of claim 1 wherein that the amount of the adenylyl cyclase conditioning agent that given does not suppress the growth of pathogenic agent.
9. the process of claim 1 wherein the amount remarkable pathogen kill not of the adenylyl cyclase conditioning agent that given.
10. the process of claim 1 wherein that described adenylyl cyclase is CO 2/ HCO 3/ pH responsive type.
11. the method for claim 10, wherein said conditioning agent influence the pathogen infection adenylyl cyclase to CO 2Reaction.
12. the method for claim 10, wherein said conditioning agent influence the pathogen infection adenylyl cyclase to HCO 3Reaction.
13. the method for claim 10, wherein said conditioning agent influence the reaction of pathogen infection adenylyl cyclase to pH.
14. the process of claim 1 wherein that the adenylyl cyclase of described pathogenic agent is an III class adenylyl cyclase.
15. the process of claim 1 wherein that described infection is caused by the pathogenic agent of anti-one or more biocides.
16. the process of claim 1 wherein that described patient is plant.
17. the process of claim 1 wherein that described patient is animal.
18. the process of claim 1 wherein that described patient is bird.
19. the method for claim 18, wherein said bird are poultry.
20. the process of claim 1 wherein that described patient is fish.
21. the process of claim 1 wherein that described patient is Mammals.
22. the method for claim 21, wherein said Mammals are domestic animal or pet.
23. the method for claim 22, wherein said domestic animal is selected from ox, pig, sheep and horse.
24. the method for claim 22, wherein said pet is selected from dog and cat.
25. the method for claim 21, wherein said Mammals is behaved.
26. the process of claim 1 wherein that described pathogenic agent adenylyl cyclase conditioning agent does not suppress patient's adenylyl cyclase.
27. the process of claim 1 wherein that described pathogenic agent adenylyl cyclase conditioning agent is optionally with respect to patient's adenylyl cyclase.
28. the process of claim 1 wherein that described pathogenic agent adenylyl cyclase conditioning agent is enough to realize therapeutic action to pathogen infection with respect to the selectivity of patient's adenylyl cyclase, and can not regulate to patient's adenylyl cyclase toxigenicity.
29. the process of claim 1 wherein that the inhibitor of described adenylyl cyclase is selected from small molecules, fit and RNA interfering.
30. the process of claim 1 wherein that the inhibitor of described adenylyl cyclase is selected from KH7.102, KH7.109, KH7.112, KH7.114, KH7.117, KH7.118, KH7.150 and combination thereof.
31. the process of claim 1 wherein that the conditioning agent of described pathogenic agent adenylyl cyclase is selected from catechol estrogen and derivative thereof.
32. further comprising, the method for claim 1, described method give one or more other therapeutical agents.
33. the method for claim 32, wherein said other therapeutical agent is a biocide.
34. a method that is used for the treatment of the disease that the patient causes by fungi infestation, described method comprises:
Give the fungi adenylyl cyclase conditioning agent of described patient treatment amount.
35. the method for claim 34, the amount of the fungi adenylyl cyclase conditioning agent that is wherein given significantly stops fungi to become pathogenic disease states by non-pathogenic disease states effectively,
The amount of the fungi adenylyl cyclase conditioning agent that is perhaps wherein given makes fungi be replied basically by pathogenic disease states to be non-pathogenic disease states effectively.
Pathogenic agent increases or reduces growth velocity 36. the method for claim 35, wherein said pathogenic agent adenylyl cyclase conditioning agent are significantly protected from infection.
37. the method for claim 35, wherein said pathogenic agent adenylyl cyclase conditioning agent reduces or significantly stops the expression of one or more virulence factors.
38. the method for claim 34, wherein said fungi adenylyl cyclase conditioning agent suppresses the fungi adenylyl cyclase.
39. the method for claim 34, wherein said fungi adenylyl cyclase conditioning agent activation fungi adenylyl cyclase.
40. the method for claim 34, wherein said fungi adenylyl cyclase conditioning agent has significant fungicidal action to infectious fungi.
41. the method for claim 34, the amount of the fungi adenylyl cyclase conditioning agent that is wherein given does not suppress fungi growth.
42. the method for claim 34, the amount of the fungi adenylyl cyclase conditioning agent that is wherein given be remarkable kill fungi not.
43. the method for claim 34, wherein said fungi adenylyl cyclase is CO 2/ HCO 3/ pH responsive type.
44. the method for claim 43, wherein said conditioning agent influence the fungal infection adenylyl cyclase to CO 2Reaction.
45. the method for claim 43, wherein said conditioning agent influence the fungal infection adenylyl cyclase to HCO 3Reaction.
46. the method for claim 43, wherein said conditioning agent influence the reaction of fungal infection adenylyl cyclase to pH.
47. the method for claim 43, wherein said fungi adenylyl cyclase are III class adenylyl cyclase.
48. the method for claim 43, wherein said infection is caused by the fungi of anti-one or more anti-mycotic agents.
49. the method for claim 34, wherein said patient is a plant.
50. the method for claim 34, wherein said patient is an animal.
51. the method for claim 34, wherein said patient is a bird.
52. the method for claim 51, wherein said bird are poultry.
53. the method for claim 34, wherein said patient is a fish.
54. the method for claim 34, wherein said patient is a Mammals.
55. the method for claim 54, wherein said Mammals are domestic animal or pet.
56. the method for claim 55, wherein said domestic animal is selected from ox, pig, sheep and horse.
57. the method for claim 55, wherein said pet is selected from dog and cat.
58. the method for claim 54, wherein said Mammals is behaved.
59. the method for claim 58, the people of wherein said artificial immune function depression.
60. the method for claim 59, the people of person's self-infection HIV of wherein said immune function depression, the people who carries out chemotherapy, patients with blood cancer, transplanting recipient, the people who accepts immunosuppressive drug, the people who accepts opium class medicine and the people who burns.
61. the method for claim 34, the conditioning agent of wherein said fungi adenylyl cyclase can significantly not suppress patient's adenylyl cyclase.
62. the method for claim 34, the conditioning agent of wherein said fungi adenylyl cyclase is optionally with respect to patient's adenylyl cyclase.
63. the method for claim 34, the conditioning agent of wherein said fungi adenylyl cyclase is enough to realize therapeutic action to fungal infection with respect to the selectivity of patient's adenylyl cyclase, and can not regulate patient's adenylyl cyclase toxigenicity.
64. the method for claim 34, the inhibitor of wherein said adenylyl cyclase are selected from small molecules, fit and RNA interfering.
65. the method for claim 35, wherein the amount of the inhibitor of the adenylyl cyclase that is given significantly stops fungi to become thread state by non-thread state effectively,
Perhaps the amount of the inhibitor of the adenylyl cyclase that is wherein given makes fungi be replied basically by thread state to be non-thread state effectively.
66. the method for claim 34, wherein said fungi are selected from Candida albicans (Candidaalbicans), Candida glabrata (Candida glabrata), Cryptococcus neoformans (Cryptococcusneoformans), Aspergillus fumigatus (Aspergillus fumigatus), Coccidioides (Coccidioides), tissue milk Pseudomonas (Histoplasma), blastomycete (Blastomyces) and blastomyces brasiliensis (Paracoccidioides).
67. the method for claim 34, the conditioning agent of wherein said adenylyl cyclase are the derivatives of density induction molecule or density induction molecule.
68. the method for claim 67, wherein said density induction molecule is the farnesol or derivatives thereof.
69. the method for claim 67, wherein said density induction molecule is N-3-oxo-C12 homoserine lactone or derivatives thereof.
70. further comprising, the method for claim 34, described method give one or more anti-mycotic agents.
71. a method that is used for the treatment of the patient who suffers from the disease that is caused by protozoal infections, described method comprises:
Give the protozoon adenylyl cyclase conditioning agent of described patient treatment amount.
72. the method for claim 71, the amount of the protozoon adenylyl cyclase conditioning agent that is wherein given significantly stops protozoon to become pathogenic disease states by non-pathogenic disease states effectively,
The amount of the protozoon adenylyl cyclase conditioning agent that is perhaps wherein given makes protozoon be replied basically by pathogenic disease states to be non-pathogenic disease states effectively.
Protozoon increases or reduces growth velocity 73. the method for claim 72, the conditioning agent of wherein said protozoon adenylyl cyclase are significantly protected from infection.
74. the method for claim 72, the conditioning agent of wherein said protozoon adenylyl cyclase reduces or significantly stops the expression of one or more virulence factors.
75. the method for claim 71, the conditioning agent of wherein said protozoon adenylyl cyclase suppresses the protozoon adenylyl cyclase.
76. the method for claim 71, the conditioning agent activation protozoon adenylyl cyclase of wherein said protozoon adenylyl cyclase.
77. the method for claim 71, the conditioning agent of wherein said protozoon adenylyl cyclase has significant protozoacide effect to infectious protozoon.
78. the method for claim 71, the amount of the protozoon adenylyl cyclase conditioning agent that is wherein given does not suppress protozoic growth.
79. the method for claim 71, the amount of the protozoon adenylyl cyclase conditioning agent that is wherein given can significantly not killed protozoon.
80. the method for claim 71, wherein said protozoon adenylyl cyclase is CO 2/ HCO 3/ pH responsive type.
81. the method for claim 80, wherein said conditioning agent influence is infected the protozoon adenylyl cyclase to CO 2Reaction.
82. the method for claim 80, wherein said conditioning agent influence is infected the protozoon adenylyl cyclase to HCO 3Reaction.
83. the method for claim 80, the reaction of protozoon adenylyl cyclase to pH infected in wherein said conditioning agent influence.
84. the method for claim 80, wherein said protozoon adenylyl cyclase are III class adenylyl cyclase.
85. the method for claim 71, wherein said infection is caused by the protozoon of anti-one or more antiprotozoals.
86. the method for claim 71, wherein said patient is a plant.
87. the method for claim 71, wherein said patient is an animal.
88. the method for claim 87, wherein said patient is a bird.
89. the method for claim 88, wherein said bird are poultry.
90. the method for claim 87, wherein said patient is a fish.
91. the method for claim 87, wherein said patient is a Mammals.
92. the method for claim 91, wherein said Mammals are domestic animal or pet.
93. the method for claim 92, wherein said domestic animal is selected from ox, pig, sheep and horse.
94. the method for claim 92, wherein said pet is selected from dog and cat.
95. the method for claim 91, wherein said Mammals is behaved.
96. the method for claim 71, the conditioning agent of wherein said protozoon adenylyl cyclase can significantly not suppress patient's adenylyl cyclase.
97. the method for claim 71, the conditioning agent of wherein said protozoon adenylyl cyclase is optionally with respect to patient's adenylyl cyclase.
98. the method for claim 71; the conditioning agent of wherein said protozoon adenylyl cyclase is enough to realize to infecting protozoic therapeutic action with respect to the selectivity of patient's adenylyl cyclase, and can not regulate patient's adenylyl cyclase toxigenicity.
99. the method for claim 71, the inhibitor of wherein said adenylyl cyclase are selected from small molecules, fit and RNA interfering.
100. the method for claim 71, wherein said protozoon is selected from following order: Gregarinia, Coccidia, Haemocytozoa and Piroplasmida.
101. the method for claim 71, wherein said protozoon is selected from: Acanthamoeba castellanii (Acanthamoeba castellanii), two bud babesias (Babesia bigemina), babesia canis (Babesia canis), separate babesia (Babesia divergens), vole babesia (Babesiamicroti), balantidium Coli (Balantidium coli), Bei Shi shellfish promise sporozoite (Besnoitiabesnoiti), cryptosporidium parvum (Cryptosporidium parvum), circle spore coccidia (Cyclospora cayetensis), eimeria tenella (Eimeria acervulina), ox eimeria tenella (Eimeria bovis), Bu Shi eimeria tenella (Eimeria brunetti), carp eimeria tenella (Eimeria carpelli), (Eimeria cyprinorum), nothing left body eimeria tenella (Eimeriairresidua), large-scale eimeria tenella (Eimeria magna), huge eimeria tenella (Eimeriamaxima), gentle eimeria tenella (Eimeria mitis), poison eimeria tenella (Eimerianecatrix), Ni Shuerci eimeria tenella (Eimeria nieschulzi), perforation eimeria tenella (Eimeria perforans), method is thought eimeria tenella (Eimeria phasiani), precocious eimeria tenella (Eimeria praecox), liver eimeria tenella (Eimeria stiedae), tender eimeria tenella (Eimeria tenella), cut shape eimeria tenella (Eimeria truncata), (Eimeriazurmii), entamoeba histolytica (Entamoeba histolytica), Lan Shi giardia lamblia (GiardiaLamblia), Leishmania donovani (Leishmania donovani), microsporidium (Microsporidia), Fu Shi Na Geli amoeba (Naeglaria flowleri), plasmodium falciparum (Plasmodium falciparum), malariae (Plasmodium malariae), Plasmodium ovale (Plasmodium ovale), Plasmodium vivax (Plasmodium vivax), Pneumocystis carinii (Pneumocystis carinii), neurone sarcocystis (Sarcocystis neurona), Sarcocystis tenella (Sarcocystis tenella), toxoplasma gondii (Toxoplasma gondii), Trichomonas vaginalis (Trichomonas vaginalis), trypanosoma bocagei (Trypanosoma brucei) and schizotrypanum cruzi (Trypanosoma cruzi).
102. the method for claim 71, the inhibitor of wherein said adenylyl cyclase is selected from KH7.102, KH7.109, KH7.112, KH7.114, KH7.117, KH7.118, KH7.150 and combination thereof.
103. further comprising, the method for claim 71, described method give one or more antiprotozoals.
104. a method that is used for the treatment of the disease that the patient infects to cause by metazoan, described method comprises:
Give the conditioning agent of the metazoan adenylyl cyclase of described patient treatment amount.
105. the method for claim 104, the amount of the metazoan adenylyl cyclase conditioning agent that is wherein given significantly stops metazoan to become pathogenic disease states by non-pathogenic disease states effectively,
The amount of the metazoan adenylyl cyclase conditioning agent that is perhaps wherein given makes metazoan be replied basically by pathogenic disease states to be non-pathogenic disease states effectively.
Metazoan increases or reduces growth velocity 106. the method for claim 105, wherein said metazoan adenylyl cyclase conditioning agent are significantly protected from infection.
107. the method for claim 104, wherein said metazoan adenylyl cyclase conditioning agent suppresses the metazoan adenylyl cyclase.
108. the method for claim 104, wherein said metazoan adenylyl cyclase conditioning agent activation metazoan adenylyl cyclase.
109. the method for claim 104, wherein said metazoan adenylyl cyclase conditioning agent has significant anti-metazoan effect to infectious metazoan.
110. the method for claim 104, the amount of the metazoan adenylyl cyclase conditioning agent that is wherein given does not suppress metazoal growth.
111. the method for claim 104, the amount of the metazoan adenylyl cyclase conditioning agent that is wherein given can significantly not killed metazoan.
112. the method for claim 104, wherein said metazoan adenylyl cyclase is CO 2/ HCO 3/ pH responsive type.
113. the method for claim 112, wherein said conditioning agent influence is infected the metazoan adenylyl cyclase to CO 2Reaction.
114. the method for claim 112, wherein said conditioning agent influence is infected the metazoan adenylyl cyclase to HCO 3Reaction.
115. the method for claim 112, the reaction of metazoan adenylyl cyclase to pH infected in wherein said conditioning agent influence.
116. the method for claim 112, wherein said metazoan adenylyl cyclase are III class adenylyl cyclase.
117. the method for claim 104, wherein said infection is caused by the metazoan of anti-one or more anti-metazoan agent.
118. the method for claim 104, wherein said patient is a plant.
119. the method for claim 104, wherein said patient is an animal.
120. the method for claim 119, wherein said patient is a bird.
121. the method for claim 120, wherein said bird are poultry.
122. the method for claim 119, wherein said patient is a fish.
123. the method for claim 119, wherein said patient is a Mammals.
124. the method for claim 123, wherein said Mammals are domestic animal or pet.
125. the method for claim 124, wherein said domestic animal is selected from ox, pig, sheep and horse.
126. the method for claim 124, wherein said pet is selected from dog and cat.
127. the method for claim 123, wherein said Mammals is behaved.
128. the method for claim 104, the conditioning agent of wherein said metazoan adenylyl cyclase can significantly not suppress patient's adenylyl cyclase.
129. the method for claim 104, the conditioning agent of wherein said metazoan adenylyl cyclase is optionally with respect to patient's adenylyl cyclase.
130. the method for claim 104; the conditioning agent of wherein said metazoan adenylyl cyclase is enough to realize metazoal therapeutic action to infecting with respect to the selectivity of patient's adenylyl cyclase, and can not regulate patient's adenylyl cyclase toxigenicity.
131. the method for claim 104, the inhibitor of wherein said adenylyl cyclase are selected from small molecules, fit and RNA interfering.
132. the method for claim 104, wherein said metazoan is selected from: taeniasis suis (Taenia solium), taeniasis bovis (Taenia saginata), fish tapeworm (Diphyllobothrium latum), Echinococcus granulosus (Echniococcus granulosus), schistosomicide (Schistosomiasis), liver fluke (Clonorchis), pinworm (Enterobius), whipworm (Tichuris), roundworm (Ascaris), hookworm (Ancylostoma), quasi-colubriformis (Strongyloides), Trichinella spiralis (Trichinella), Anisakid nematode (Anisakis), Wuchereria (Wuchereria), filaria volvulus (Onchocerca), Loa loa (Loa), dragon nematode (Dracuncululs) and bow roundworm (Toxocara).
133. the method for claim 104, the inhibitor of wherein said adenylyl cyclase is selected from KH7.102, KH7.109, KH7.112, KH7.114, KH7.117, KH7.118, KH7.150 and combination thereof.
134. further comprising, the method for claim 104, described method give one or more anti-metazoan agent.
135. one kind is used to prevent the patient to infect the method for the disease that causes by eukaryotic pathogens, described method comprises:
Give the conditioning agent of the eukaryotic pathogens adenylyl cyclase of described patient treatment amount.
136. the method for claim 135, the amount of the conditioning agent of the pathogenic agent adenylyl cyclase that is wherein given significantly stop pathogenic agent to become pathogenic disease states by non-pathogenic disease states effectively,
The amount of the conditioning agent of the pathogenic agent adenylyl cyclase that is perhaps wherein given makes pathogenic agent be replied basically by pathogenic disease states to be non-pathogenic disease states effectively.
Pathogenic agent increases or reduces growth velocity 137. the method for claim 136, the conditioning agent of wherein said pathogenic agent adenylyl cyclase significantly prevent infections.
138. the method for claim 136, the conditioning agent of wherein said adenylyl cyclase reduces or significantly stops the expression of one or more virulence factors.
139. the method for claim 135, the conditioning agent of wherein said pathogenic agent adenylyl cyclase suppresses the pathogenic agent adenylyl cyclase.
140. the method for claim 135, the conditioning agent activation pathogenic agent adenylyl cyclase of wherein said pathogenic agent adenylyl cyclase.
141. the method for claim 135, the conditioning agent of wherein said pathogenic agent adenylyl cyclase has significant biocidal effect to infectious pathogen.
142. the method for claim 135, wherein the amount of the conditioning agent of the adenylyl cyclase that is given does not suppress the growth of pathogenic agent.
143. the method for claim 135, the amount of the adenylyl cyclase conditioning agent that is wherein given be remarkable pathogen kill not.
144. the method for claim 135, wherein said adenylyl cyclase are CO 2/ HCO 3/ pH responsive type.
145. the method for claim 144, wherein said conditioning agent influence the pathogen infection adenylyl cyclase to CO 2Reaction.
146. the method for claim 144, wherein said conditioning agent influence the pathogen infection adenylyl cyclase to HCO 3Reaction.
147. the method for claim 144, wherein said conditioning agent influence the reaction of pathogen infection adenylyl cyclase to pH.
148. the method for claim 135, wherein said pathogenic agent adenylyl cyclase are III class adenylyl cyclase.
149. the method for claim 135, wherein said infection is caused by the pathogenic agent of anti-one or more biocides.
150. the method for claim 135, wherein said patient is a plant.
151. the method for claim 135, wherein said patient is an animal.
152. the method for claim 135, wherein said patient is a bird.
153. the method for claim 152, wherein said bird are poultry.
154. the method for claim 135, wherein said patient is a fish.
155. the method for claim 135, wherein said patient is a Mammals.
156. the method for claim 155, wherein said Mammals are domestic animal or pet.
157. the method for claim 156, wherein said domestic animal is selected from ox, pig, sheep and horse.
158. the method for claim 156, wherein said pet is selected from dog and cat.
159. the method for claim 155, wherein said Mammals is behaved.
160. the method for claim 135, the conditioning agent of wherein said pathogenic agent adenylyl cyclase does not suppress patient's adenylyl cyclase.
161. the method for claim 135, the conditioning agent of wherein said pathogenic agent adenylyl cyclase is optionally with respect to patient's adenylyl cyclase.
162. the method for claim 135, the conditioning agent of wherein said pathogenic agent adenylyl cyclase is enough to realize therapeutic action to pathogen infection with respect to the selectivity of patient's adenylyl cyclase, and can not regulate patient's adenylyl cyclase toxigenicity.
163. the method for claim 135, the inhibitor of wherein said adenylyl cyclase are selected from small molecules, fit and RNA interfering.
164. the method for claim 163, the inhibitor of wherein said adenylyl cyclase is selected from KH7.102, KH7.109, KH7.112, KH7.114, KH7.117, KH7.118, KH7.150 and combination thereof.
165. the method for claim 163, the conditioning agent of wherein said pathogenic agent adenylyl cyclase is selected from catechol estrogen and derivative thereof.
166. further comprising, the method for claim 135, described method give one or more other therapeutical agents.
167. the method for claim 166, wherein said other therapeutical agent is a biocide.
168. a method that is used to prevent the disease that the patient causes by fungi infestation, described method comprises:
Give the conditioning agent of the fungi adenylyl cyclase of described patient treatment amount.
169. the method for claim 168, the amount of the fungi adenylyl cyclase conditioning agent that is wherein given significantly stops fungi to become pathogenic disease states by non-pathogenic disease states effectively,
The amount of the fungi adenylyl cyclase conditioning agent that is perhaps wherein given makes fungi be replied basically by pathogenic disease states to be non-pathogenic disease states effectively.
Fungi increases or reduces growth velocity 170. the method for claim 169, wherein said fungi adenylyl cyclase conditioning agent are significantly protected from infection.
171. the method for claim 169, wherein said fungi adenylyl cyclase conditioning agent reduces or significantly stops the expression of one or more virulence factors.
172. the method for claim 168, wherein said fungi adenylyl cyclase conditioning agent suppresses the fungi adenylyl cyclase.
173. the method for claim 168, wherein said fungi adenylyl cyclase conditioning agent activation fungi adenylyl cyclase.
174. the method for claim 168, wherein said fungi adenylyl cyclase conditioning agent has significant fungicidal action to infectious fungi.
175. the method for claim 168, the amount of the fungi adenylyl cyclase conditioning agent that is wherein given does not suppress fungi growth.
176. the method for claim 168, the amount of the fungi adenylyl cyclase conditioning agent that is wherein given be remarkable kill fungi not.
177. the method for claim 168, wherein said fungi adenylyl cyclase is CO 2/ HCO 3/ pH responsive type.
178. the method for claim 177, wherein said conditioning agent influence the pathogen infection adenylyl cyclase to CO 2Reaction.
179. the method for claim 177, wherein said conditioning agent influence the pathogen infection adenylyl cyclase to HCO 3Reaction.
180. the method for claim 177, wherein said conditioning agent influence the reaction of pathogen infection adenylyl cyclase to pH.
181. the method for claim 177, wherein said fungi adenylyl cyclase are III class adenylyl cyclase.
182. the method for claim 168, wherein said infection is caused by the fungi of anti-one or more anti-mycotic agents.
183. the method for claim 168, wherein said patient is a plant.
184. the method for claim 168, wherein said patient is an animal.
185. the method for claim 168, wherein said patient is a bird.
186. the method for claim 185, wherein said bird are poultry.
187. the method for claim 168, wherein said patient is a fish.
188. the method for claim 168, wherein said patient is a Mammals.
189. the method for claim 188, wherein said Mammals are domestic animal or pet.
190. the method for claim 189, wherein said domestic animal is selected from ox, pig, sheep and horse.
191. the method for claim 189, wherein said pet is selected from dog and cat.
192. the method for claim 188, wherein said Mammals is behaved.
193. the method for claim 192, the people of wherein said artificial immune function depression.
194. the method for claim 193, the people of person's self-infection HIV of wherein said immune function depression, the people who carries out chemotherapy, patients with blood cancer, transplanting recipient, the people who accepts immunosuppressive drug, the people who accepts opium class medicine and the people who burns.
195. the method for claim 168, the conditioning agent of wherein said fungi adenylyl cyclase can significantly not suppress patient's adenylyl cyclase.
196. the method for claim 168, the conditioning agent of wherein said fungi adenylyl cyclase is optionally with respect to patient's adenylyl cyclase.
197. the method for claim 168, the conditioning agent of wherein said fungi adenylyl cyclase is enough to realize therapeutic action to fungal infection with respect to the selectivity of patient's adenylyl cyclase, and can not regulate patient's adenylyl cyclase toxigenicity.
198. the method for claim 168, the inhibitor of wherein said adenylyl cyclase are selected from small molecules, fit and RNA interfering.
199. the method for claim 169, wherein the amount of the inhibitor of the adenylyl cyclase that is given significantly stops fungi to become thread state by non-thread state effectively,
Perhaps the amount of the inhibitor of the adenylyl cyclase that is wherein given makes fungi be replied basically by thread state to be non-thread state effectively.
200. the method for claim 168, wherein said fungi are selected from Candida albicans (Candida albicans), Candida glabrata (Candida glabrata), Cryptococcus neoformans (Cryptococcus neoformans), Aspergillus fumigatus (Aspergillus fumigatus), Coccidioides (Coccidioides), tissue milk Pseudomonas (Histoplasma), blastomycete (Blastomyces) and blastomyces brasiliensis (Paracoccidioides).
201. the method for claim 168, the conditioning agent of wherein said adenylyl cyclase are the derivatives of density induction molecule or density induction molecule.
202. the method for claim 201, wherein said density induction molecule is the farnesol or derivatives thereof.
203. the method for claim 201, wherein said density induction molecule is N-3-oxo-C12 homoserine lactone or derivatives thereof.
204. further comprising, the method for claim 166, described method give one or more anti-mycotic agents.
205. one kind is used to prevent the patient to cause the method for disease by protozoal infections, described method comprises:
Give the conditioning agent of the protozoon adenylyl cyclase of described patient treatment amount.
206. the method for claim 205, the amount of the conditioning agent of the protozoon adenylyl cyclase that is wherein given significantly stop protozoon to become pathogenic disease states by non-pathogenic disease states effectively,
The amount of the conditioning agent of the protozoon adenylyl cyclase that is perhaps wherein given makes protozoon be replied basically by pathogenic disease states to be non-pathogenic disease states effectively.
Protozoon increases or reduces growth velocity 207. the method for claim 206, the conditioning agent of wherein said protozoon adenylyl cyclase are significantly protected from infection.
208. the method for claim 206, the conditioning agent of wherein said protozoon adenylyl cyclase reduces or significantly stops the expression of one or more virulence factors.
209. the method for claim 205, the conditioning agent of wherein said protozoon adenylyl cyclase suppresses the protozoon adenylyl cyclase.
210. the method for claim 205, the conditioning agent activation protozoon adenylyl cyclase of wherein said protozoon adenylyl cyclase.
211. the method for claim 205, the conditioning agent of wherein said protozoon adenylyl cyclase has significant protozoacide effect to infectious protozoon.
212. the method for claim 205, the amount of the conditioning agent of the protozoon adenylyl cyclase that is wherein given does not suppress protozoic growth.
213. the method for claim 205, the amount of the conditioning agent of the protozoon adenylyl cyclase that is wherein given can significantly not killed protozoon.
214. the method for claim 205, wherein said protozoon adenylyl cyclase is CO 2/ HCO 3/ pH responsive type.
215. the method for claim 214, wherein said conditioning agent influence is infected the protozoon adenylyl cyclase to CO 2Reaction.
216. the method for claim 214, wherein said conditioning agent influence is infected the protozoon adenylyl cyclase to HCO 3Reaction.
217. the method for claim 214, the reaction of protozoon adenylyl cyclase to pH infected in wherein said conditioning agent influence.
218. the method for claim 214, wherein said protozoon adenylyl cyclase are III class adenylyl cyclase.
219. the method for claim 205, wherein said infection is caused by the fungi of anti-one or more antiprotozoals.
220. the method for claim 205, wherein said patient is a plant.
221. the method for claim 205, wherein said patient is an animal.
222. the method for claim 205, wherein said patient is a bird.
223. the method for claim 222, wherein said bird are poultry.
224. the method for claim 205, wherein said patient is a fish.
225. the method for claim 205, wherein said patient is a Mammals.
226. the method for claim 225, wherein said Mammals are domestic animal or pet.
227. the method for claim 226, wherein said domestic animal is selected from ox, pig, sheep and horse.
228. the method for claim 226, wherein said pet is selected from dog and cat.
229. the method for claim 225, wherein said Mammals is behaved.
230. the method for claim 205, the conditioning agent of wherein said protozoon adenylyl cyclase can significantly not suppress patient's adenylyl cyclase.
231. the method for claim 205, the conditioning agent of wherein said protozoon adenylyl cyclase is optionally with respect to patient's adenylyl cyclase.
232. the method for claim 205; the conditioning agent of wherein said protozoon adenylyl cyclase is enough to realize to infecting protozoic therapeutic action with respect to the selectivity of patient's adenylyl cyclase, and can not regulate patient's adenylyl cyclase toxigenicity.
233. the method for claim 205, the inhibitor of wherein said adenylyl cyclase are selected from small molecules, fit and RNA interfering.
234. the method for claim 205, wherein said protozoon is selected from following order: Gregarinia, Coccidia, Haemocytozoa and Piroplasmida.
235. the method for claim 205, wherein said protozoon is selected from: Acanthamoeba castellanii (Acanthamoeba castellanii), two bud babesias (Babesia bigemina), babesia canis (Babesia canis), separate babesia (Babesia divergens), vole babesia (Babesiamicroti), balantidium Coli (Balantidium coli), Bei Shi shellfish promise sporozoite (Besnoitiabesnoiti), cryptosporidium parvum (Cryptosporidium parvum), circle spore coccidia (Cyclospora cayetensis), eimeria tenella (Eimeria acervulina), ox eimeria tenella (Eimeria bovis), Bu Shi eimeria tenella (Eimeria brunetti), carp eimeria tenella (Eimeria carpelli), (Eimeria cyprinorum), nothing left body eimeria tenella (Eimeriairresidua), large-scale eimeria tenella (Eimeria magna), huge eimeria tenella (Eimeriamaxima), gentle eimeria tenella (Eimeria mitis), poison eimeria tenella (Eimerianecatrix), Ni Shuerci eimeria tenella (Eimeria nieschulzi), perforation eimeria tenella (Eimeria perforans), method is thought eimeria tenella (Eimeria phasiani), precocious eimeria tenella (Eimeria praecox), liver eimeria tenella (Eimeria stiedae), tender eimeria tenella (Eimeria tenella), cut shape eimeria tenella (Eimeria truncata), (Eimeriazurmii), entamoeba histolytica (Entamoeba histolyica), Lan Shi giardia lamblia (GiardiaLamblia), Leishmania donovani (Leishmania donovani), microsporidium (Microsporidia), Fu Shi Na Geli amoeba (Naeglaria flowleri), plasmodium falciparum (Plasmodium falciparum), malariae (Plasmodium malariae), Plasmodium ovale (Plasmodium ovale), Plasmodium vivax (Plasmodium vivax), Pneumocystis carinii (Pneumocystis carinii), neurone sarcocystis (Sarcocystis neurona), Sarcocystis tenella (Sarcocystis tenella), toxoplasma gondii (Toxoplasma gondii), Trichomonas vaginalis (Trichomonas vaginalis), trypanosoma bocagei (Trypanosoma brucei) and schizotrypanum cruzi (Trypanosoma cruzi).
236. the method for claim 205, the inhibitor of wherein said adenylyl cyclase is selected from KH7.102, KH7.109, KH7.112, KH7.114, KH7.117, KH7.118, KH7.150 and combination thereof.
237. further comprising, the method for claim 205, described method give one or more antiprotozoals.
238. a method that is used for the treatment of the disease that the patient infects to cause by metazoan, described method comprises:
Give the conditioning agent of the metazoan adenylyl cyclase of described patient treatment amount.
239. the method for claim 238, the amount of the metazoan adenylyl cyclase conditioning agent that is wherein given significantly stops metazoan to become pathogenic disease states by non-pathogenic disease states effectively,
The amount of the metazoan adenylyl cyclase conditioning agent that is perhaps wherein given makes metazoan be replied basically by pathogenic disease states to be non-pathogenic disease states effectively.
Metazoan increases or reduces growth velocity 240. the method for claim 239, the conditioning agent of wherein said metazoan adenylyl cyclase are significantly protected from infection.
241. the method for claim 238, the conditioning agent of wherein said metazoan adenylyl cyclase suppresses the metazoan adenylyl cyclase.
242. the method for claim 238, the conditioning agent activation metazoan adenylyl cyclase of wherein said metazoan adenylyl cyclase.
243. the method for claim 238, the conditioning agent of wherein said metazoan adenylyl cyclase has significant anti-metazoan effect to infectious metazoan.
244. the method for claim 238, the amount of the conditioning agent of the metazoan adenylyl cyclase that is wherein given does not suppress metazoal growth.
245. the method for claim 238, the amount of the metazoan adenylyl cyclase conditioning agent that is wherein given can significantly not killed metazoan.
246. the method for claim 238, wherein said metazoan adenylyl cyclase is CO 2/ HCO 3/ pH responsive type.
247. the method for claim 246, wherein said conditioning agent influence is infected the metazoan adenylyl cyclase to CO 2Reaction.
248. the method for claim 246, wherein said conditioning agent influence is infected the metazoan adenylyl cyclase to HCO 3Reaction.
249. the method for claim 246, the reaction of metazoan adenylyl cyclase to pH infected in wherein said conditioning agent influence.
250. the method for claim 246, wherein said metazoan adenylyl cyclase are III class adenylyl cyclase.
251. the method for claim 238, wherein said infection is caused by the metazoan of anti-one or more anti-metazoan agent.
252. the method for claim 238, wherein said patient is a plant.
253. the method for claim 238, wherein said patient is an animal.
254. the method for claim 238, wherein said patient is a bird.
255. the method for claim 254, wherein said bird are poultry.
256. the method for claim 238, wherein said patient is a fish.
257. the method for claim 238, wherein said patient is a Mammals.
258. the method for claim 257, wherein said Mammals are domestic animal or pet.
259. the method for claim 258, wherein said domestic animal is selected from ox, pig, sheep and horse.
260. the method for claim 258, wherein said pet is selected from dog and cat.
261. the method for claim 257, wherein said Mammals is behaved.
262. the method for claim 238, the conditioning agent of wherein said metazoan adenylyl cyclase can significantly not suppress patient's adenylyl cyclase.
263. the method for claim 238, the conditioning agent of wherein said metazoan adenylyl cyclase is optionally with respect to patient's adenylyl cyclase.
264. the method for claim 238; the conditioning agent of wherein said metazoan adenylyl cyclase is enough to realize to infecting metazoal therapeutic action with respect to the selectivity of patient's adenylyl cyclase, and can not regulate patient's adenylyl cyclase toxigenicity.
265. the method for claim 238, the inhibitor of wherein said adenylyl cyclase are selected from small molecules, fit and RNA interfering.
266. the method for claim 238, wherein said metazoan is selected from: taeniasis suis (Taenia solium), taeniasis bovis (Taenia saginata), fish tapeworm (Diphyllobothrium latum), Echinococcus granulosus (Echniococcus granulosus), schistosomicide (Schistosomiasis), liver fluke (Clonorchis), pinworm (Enterobius), whipworm (Tichuris), roundworm (Ascaris), hookworm (Ancylostoma), quasi-colubriformis (Strongyloides), Trichinella spiralis (Trichinella), Anisakid nematode (Anisakis), Wuchereria (Wuchereria), filaria volvulus (Onchocerca), Loa loa (Loa), dragon nematode (Dracuncululs) and bow roundworm (Toxocara).
267. the method for claim 238, the inhibitor of wherein said adenylyl cyclase is selected from KH7.102, KH7.109, KH7.112, KH7.114, KH7.117, KH7.118, KH7.150 and combination thereof.
268. further comprising, the method for claim 238, described method give one or more anti-metazoan agent.
269. pharmaceutical composition that contains the eukaryotic pathogens adenylyl cyclase conditioning agent for the treatment of significant quantity.
270. the pharmaceutical composition of claim 269, the amount of the pathogenic agent adenylyl cyclase conditioning agent that is wherein given significantly stops pathogenic agent to become pathogenic disease states by non-pathogenic disease states effectively,
The amount of the pathogenic agent adenylyl cyclase conditioning agent that is perhaps wherein given makes pathogenic agent be replied basically by pathogenic disease states to be non-pathogenic disease states effectively.
Pathogenic agent increases or reduces growth velocity 271. the pharmaceutical composition of claim 270, the conditioning agent of wherein said pathogenic agent adenylyl cyclase are significantly protected from infection.
272. the pharmaceutical composition of claim 269, the conditioning agent of wherein said pathogenic agent adenylyl cyclase reduces or significantly stops the expression of one or more virulence factors.
273. the pharmaceutical composition of claim 269, the conditioning agent of wherein said pathogenic agent adenylyl cyclase suppresses the pathogenic agent adenylyl cyclase.
274. the pharmaceutical composition of claim 269, the conditioning agent activation pathogenic agent adenylyl cyclase of wherein said pathogenic agent adenylyl cyclase.
275. the pharmaceutical composition of claim 269, the conditioning agent of wherein said pathogenic agent adenylyl cyclase has significant biocidal effect to infectious pathogen.
276. the pharmaceutical composition of claim 269, the amount of the adenylyl cyclase conditioning agent that is wherein given does not suppress the growth of pathogenic agent.
277. the pharmaceutical composition of claim 269, the amount of the adenylyl cyclase conditioning agent that is wherein given be remarkable pathogen kill not.
278. the pharmaceutical composition of claim 269, wherein said adenylyl cyclase are CO 2/ HCO 3/ pH responsive type.
279. the pharmaceutical composition of claim 278, wherein said conditioning agent influence the pathogen infection adenylyl cyclase to CO 2Reaction.
280. the pharmaceutical composition of claim 278, wherein said conditioning agent influence the pathogen infection adenylyl cyclase to HCO 3Reaction.
281. the pharmaceutical composition of claim 278, wherein said conditioning agent influence the reaction of pathogen infection adenylyl cyclase to pH.
282. the pharmaceutical composition of claim 278, wherein said pathogenic agent adenylyl cyclase are III class adenylyl cyclase.
283. the pharmaceutical composition of claim 269, wherein said infection is caused by the pathogenic agent of anti-one or more biocides.
284. the pharmaceutical composition of claim 269, wherein said patient is a plant.
285. the pharmaceutical composition of claim 269, wherein said patient is an animal.
286. the pharmaceutical composition of claim 269, wherein said patient is a bird.
287. the pharmaceutical composition of claim 286, wherein said bird are poultry.
288. the pharmaceutical composition of claim 269, wherein said patient is a fish.
289. the pharmaceutical composition of claim 269, wherein said patient is a Mammals.
290. the pharmaceutical composition of claim 289, wherein said Mammals are domestic animal or pet.
291. the pharmaceutical composition of claim 290, wherein said domestic animal is selected from ox, pig, sheep and horse.
292. the pharmaceutical composition of claim 290, wherein said pet is selected from dog and cat.
293. the pharmaceutical composition of claim 289, wherein said Mammals is behaved.
294. the pharmaceutical composition of claim 269, the conditioning agent of wherein said pathogenic agent adenylyl cyclase does not suppress patient's adenylyl cyclase.
295. the pharmaceutical composition of claim 269, the conditioning agent of wherein said pathogenic agent adenylyl cyclase is optionally with respect to patient's adenylyl cyclase.
296. the pharmaceutical composition of claim 269; the conditioning agent of wherein said pathogenic agent adenylyl cyclase is enough to realize therapeutic action to pathogen infection with respect to the selectivity of patient's adenylyl cyclase, and can not regulate patient's adenylyl cyclase toxigenicity.
297. the pharmaceutical composition of claim 269, the inhibitor of wherein said adenylyl cyclase are selected from small molecules, fit and RNA interfering.
298. the pharmaceutical composition of claim 297, the inhibitor of wherein said adenylyl cyclase is selected from KH7.102, KH7.109, KH7.112, KH7.114, KH7.117, KH7.118, KH7.150 and combination thereof.
299. the pharmaceutical composition of claim 269, the conditioning agent of wherein said pathogenic agent adenylyl cyclase is selected from catechol estrogen and derivative thereof.
300. further comprising, the pharmaceutical composition of claim 269, described method give one or more other therapeutical agents.
301. the pharmaceutical composition of claim 300, wherein said other therapeutical agent is a biocide.
302. the pharmaceutical composition of claim 269, wherein said conditioning agent transmits in pharmaceutically acceptable vehicle.
303. the pharmaceutical composition of claim 269, wherein said composition are oral dosage form.
304. the pharmaceutical composition of claim 269, wherein said composition are parenteral dosage form.
305. a pharmaceutical composition, described composition contain the fungi adenylyl cyclase conditioning agent for the treatment of significant quantity.
306. the pharmaceutical composition of claim 305, the amount of the fungi adenylyl cyclase conditioning agent that is wherein given significantly stops fungi to become pathogenic disease states by non-pathogenic disease states effectively,
The amount of the fungi adenylyl cyclase conditioning agent that is perhaps wherein given makes fungi be replied basically by pathogenic disease states to be non-pathogenic disease states effectively.
Pathogenic agent increases or reduces growth velocity 307. the pharmaceutical composition of claim 306, the conditioning agent of wherein said pathogenic agent adenylyl cyclase are significantly protected from infection.
308. the pharmaceutical composition of claim 305, the conditioning agent of wherein said pathogenic agent adenylyl cyclase reduces or significantly stops the expression of one or more virulence factors.
309. the pharmaceutical composition of claim 305, the conditioning agent of wherein said fungi adenylyl cyclase suppresses the fungi adenylyl cyclase.
310. the pharmaceutical composition of claim 305, the conditioning agent activation fungi adenylyl cyclase of wherein said fungi adenylyl cyclase.
311. the pharmaceutical composition of claim 305, the conditioning agent of wherein said fungi adenylyl cyclase has significant fungicidal action to infectious fungi.
312. the pharmaceutical composition of claim 305, the amount of the fungi adenylyl cyclase conditioning agent that is wherein given does not suppress fungi growth.
313. the pharmaceutical composition of claim 305, the amount of the fungi adenylyl cyclase conditioning agent that is wherein given be remarkable kill fungi not.
314. the pharmaceutical composition of claim 305, wherein said fungi adenylyl cyclase is CO 2/ HCO 3/ pH responsive type.
315. the pharmaceutical composition of claim 314, wherein said conditioning agent influence the fungal infection adenylyl cyclase to CO 2Reaction.
316. the pharmaceutical composition of claim 314, wherein said conditioning agent influence the fungal infection adenylyl cyclase to HCO 3Reaction.
317. the pharmaceutical composition of claim 314, wherein said conditioning agent influence the reaction of fungal infection adenylyl cyclase to pH.
318. the pharmaceutical composition of claim 314, wherein said pathogenic agent adenylyl cyclase are III class adenylyl cyclase.
319. the pharmaceutical composition of claim 305, wherein said infection is caused by the fungi of anti-one or more anti-mycotic agents.
320. the pharmaceutical composition of claim 305, wherein said patient is a plant.
321. the pharmaceutical composition of claim 305, wherein said patient is an animal.
322. the pharmaceutical composition of claim 305, wherein said patient is a bird.
323. the pharmaceutical composition of claim 322, wherein said bird are poultry.
324. the pharmaceutical composition of claim 305, wherein said patient is a fish.
325. the pharmaceutical composition of claim 305, wherein said patient is a Mammals.
326. the pharmaceutical composition of claim 325, wherein said Mammals are domestic animal or pet.
327. the pharmaceutical composition of claim 326, wherein said domestic animal is selected from ox, pig, sheep and horse.
328. the pharmaceutical composition of claim 326, wherein said pet is selected from dog and cat.
329. the pharmaceutical composition of claim 325, wherein said Mammals is behaved.
330. the pharmaceutical composition of claim 329, the people of wherein said artificial immune function depression.
331. the pharmaceutical composition of claim 330, the people of person's self-infection HIV of wherein said immune function depression, the people who carries out chemotherapy, patients with blood cancer, transplanting recipient, the people who accepts immunosuppressive drug, the people who accepts opium class medicine and the people who burns.
332. the pharmaceutical composition of claim 305, the conditioning agent of wherein said fungi adenylyl cyclase can significantly not suppress patient's adenylyl cyclase.
333. the pharmaceutical composition of claim 305, the conditioning agent of wherein said fungi adenylyl cyclase is optionally with respect to patient's adenylyl cyclase.
334. the pharmaceutical composition of claim 305; the conditioning agent of wherein said fungi adenylyl cyclase is enough to realize therapeutic action to fungal infection with respect to the selectivity of patient's adenylyl cyclase, and can not regulate patient's adenylyl cyclase toxigenicity.
335. the pharmaceutical composition of claim 305, the inhibitor of wherein said adenylyl cyclase are selected from small molecules, fit and RNA interfering.
336. the pharmaceutical composition of claim 306, wherein the amount of the inhibitor of the adenylyl cyclase that is given significantly stops fungi to become thread state by non-thread state effectively,
Perhaps the amount of the inhibitor of the adenylyl cyclase that is wherein given makes fungi be replied basically by thread state to be non-thread state effectively.
337. the pharmaceutical composition of claim 305, wherein said fungi are selected from Candida albicans (Candida albicans), Candida glabrata (Candida glabrata), Cryptococcus neoformans (Cryptococcus neoformans), Aspergillus fumigatus (Aspergillus fumigatus), Coccidioides (Coccidioides), tissue milk Pseudomonas (Histoplasma), blastomycete (Blastomyces) and blastomyces brasiliensis (Paracoccidioides).
338. the pharmaceutical composition of claim 305, the conditioning agent of wherein said adenylyl cyclase are the derivatives of density induction molecule or density induction molecule.
339. the pharmaceutical composition of claim 338, wherein said density induction molecule is the farnesol or derivatives thereof.
340. the pharmaceutical composition of claim 338, wherein said density induction molecule is N-3-oxo-C12 homoserine lactone or derivatives thereof.
341. further comprising, the pharmaceutical composition of claim 305, described method give one or more anti-mycotic agents.
342. the pharmaceutical composition of claim 305, wherein said conditioning agent transmits in pharmaceutically acceptable vehicle.
343. the pharmaceutical composition of claim 305, wherein said composition are oral dosage form.
344. the pharmaceutical composition of claim 305, wherein said composition are parenteral dosage form.
345. a pharmaceutical composition, described composition contain the protozoon adenylyl cyclase conditioning agent for the treatment of significant quantity.
346. the pharmaceutical composition of claim 345, the amount of the protozoon adenylyl cyclase conditioning agent that is wherein given significantly stops protozoon to become pathogenic disease states by non-pathogenic disease states effectively,
The amount of the protozoon adenylyl cyclase conditioning agent that is perhaps wherein given makes protozoon be replied basically by pathogenic disease states to be non-pathogenic disease states effectively.
Protozoon increases or reduces growth velocity 347. the pharmaceutical composition of claim 346, the conditioning agent of wherein said protozoon adenylyl cyclase are significantly protected from infection.
348. the pharmaceutical composition of claim 346, the conditioning agent of wherein said protozoon adenylyl cyclase reduces or significantly stops the expression of one or more virulence factors.
349. the pharmaceutical composition of claim 345, the conditioning agent of wherein said protozoon adenylyl cyclase suppresses the protozoon adenylyl cyclase.
350. the pharmaceutical composition of claim 345, the conditioning agent activation protozoon adenylyl cyclase of wherein said protozoon adenylyl cyclase.
351. the pharmaceutical composition of claim 345, the conditioning agent of wherein said protozoon adenylyl cyclase has significant protozoacide effect to infectious protozoon.
352. the pharmaceutical composition of claim 345, the amount of the protozoon adenylyl cyclase conditioning agent that is wherein given does not suppress protozoic growth.
353. the pharmaceutical composition of claim 345, the amount of the protozoon adenylyl cyclase conditioning agent that is wherein given can significantly not killed protozoon.
354. the pharmaceutical composition of claim 345, wherein said protozoon adenylyl cyclase is CO 2/ HCO 3/ pH responsive type.
355. the pharmaceutical composition of claim 354, wherein said conditioning agent influence is infected the protozoon adenylyl cyclase to CO 2Reaction.
356. the pharmaceutical composition of claim 354, wherein said conditioning agent influence is infected the protozoon adenylyl cyclase to HCO 3Reaction.
357. the pharmaceutical composition of claim 354, the reaction of protozoon adenylyl cyclase to pH infected in wherein said conditioning agent influence.
358. the pharmaceutical composition of claim 354, wherein said protozoon adenylyl cyclase are III class adenylyl cyclase.
359. the pharmaceutical composition of claim 345, wherein said infection is caused by the protozoon of anti-one or more antiprotozoals.
360. the pharmaceutical composition of claim 345, wherein said patient is a plant.
361. the pharmaceutical composition of claim 345, wherein said patient is an animal.
362. the pharmaceutical composition of claim 345, wherein said patient is a bird.
363. the pharmaceutical composition of claim 362, wherein said bird are poultry.
364. the pharmaceutical composition of claim 345, wherein said patient is a fish.
365. the pharmaceutical composition of claim 345, wherein said patient is a Mammals.
366. the pharmaceutical composition of claim 345, wherein said Mammals are domestic animal or pet.
367. the pharmaceutical composition of claim 366, wherein said domestic animal is selected from ox, pig, sheep and horse.
368. the pharmaceutical composition of claim 366, wherein said pet is selected from dog and cat.
369. the pharmaceutical composition of claim 345, wherein said Mammals is behaved.
370. the pharmaceutical composition of claim 345, the conditioning agent of wherein said protozoon adenylyl cyclase can significantly not suppress patient's adenylyl cyclase.
371. the pharmaceutical composition of claim 345, the conditioning agent of wherein said protozoon adenylyl cyclase is optionally with respect to patient's adenylyl cyclase.
372. the pharmaceutical composition of claim 345; the conditioning agent of wherein said protozoon adenylyl cyclase is enough to realize to infecting protozoic therapeutic action with respect to the selectivity of patient's adenylyl cyclase, and can not regulate patient's adenylyl cyclase toxigenicity.
373. the pharmaceutical composition of claim 345, the inhibitor of wherein said adenylyl cyclase are selected from small molecules, fit and RNA interfering.
374. the pharmaceutical composition of claim 345, wherein said protozoon is selected from following order: Gregarinia, Coccidia, Haemocytozoa and Piroplasmida.
375. the pharmaceutical composition of claim 345, wherein said protozoon is selected from: Acanthamoeba castellanii (Acanthamoeba castellanii), two bud babesias (Babesia bigemina), babesia canis (Babesia canis), separate babesia (Babesia divergens), vole babesia (Babesia microti), balantidium Coli (Balantidium coli), Bei Shi shellfish promise sporozoite (Besnoitia besnoiti), cryptosporidium parvum (Cryptosporidium parvum), circle spore coccidia (Cyclospora cayetensis), eimeria tenella (Eimeria acervulina), ox eimeria tenella (Eimeria bovis), Bu Shi eimeria tenella (Eimeria brunetti), carp eimeria tenella (Eimeria carpelli), (Eimeria cyprinorum), nothing left body eimeria tenella (Eimeria irresidua), large-scale eimeria tenella (Eimeria magna), huge eimeria tenella (Eimeria maxima), gentle eimeria tenella (Eimeria mitis), poison eimeria tenella (Eimeria necatrix), Ni Shuerci eimeria tenella (Eimeria nieschulzi), perforation eimeria tenella (Eimeria perforans), method is thought eimeria tenella (Eimeria phasiani), precocious eimeria tenella (Eimeria praecox), liver eimeria tenella (Eimeria stiedae), tender eimeria tenella (Eimeria tenella), cut shape eimeria tenella (Eimeria truncata), (Eimeria zurmii), entamoeba histolytica (Entamoeba histolytica), Lan Shi giardia lamblia (Giardia Lamblia), Leishmania donovani (Leishmania donovani), microsporidium (Microsporidia), Fu Shi Na Geli amoeba (Naeglaria flowleri), plasmodium falciparum (Plasmodium falciparum), malariae (Plasmodium malariae), Plasmodium ovale (Plasmodium ovale), Plasmodium vivax (Plasmodium vivax), Pneumocystis carinii (Pneumocystis carinii), neurone sarcocystis (Sarcocystis neurona), Sarcocystis tenella (Sarcocystis tenella), toxoplasma gondii (Toxoplasma gondii), Trichomonas vaginalis (Trichomonas vaginalis), trypanosoma bocagei (Trypanosoma brucei) and schizotrypanum cruzi (Trypanosoma cruzi).
376. the pharmaceutical composition of claim 345, the inhibitor of wherein said adenylyl cyclase is selected from KH7.102, KH7.109, KH7.112, KH7.114, KH7.117, KH7.118, KH7.150 and combination thereof.
377. further comprising, the pharmaceutical composition of claim 345, described composition give one or more antiprotozoals.
378. the pharmaceutical composition of claim 345, wherein said conditioning agent transmits in pharmaceutically acceptable vehicle.
379. the pharmaceutical composition of claim 345, wherein said composition are oral dosage form.
380. the pharmaceutical composition of claim 345, wherein said composition are parenteral dosage form.
381. a pharmaceutical composition, described composition contain the conditioning agent of the metazoan adenylyl cyclase for the treatment of significant quantity.
382. the pharmaceutical composition of claim 381, the amount of the metazoan adenylyl cyclase conditioning agent that is wherein given significantly stops metazoan to become pathogenic disease states by non-pathogenic disease states effectively,
The amount of the metazoan adenylyl cyclase conditioning agent that is perhaps wherein given makes metazoan be replied basically by pathogenic disease states to be non-pathogenic disease states effectively.
Metazoan increases or reduces growth velocity 383. the pharmaceutical composition of claim 382, the conditioning agent of wherein said metazoan adenylyl cyclase are significantly protected from infection.
384. the pharmaceutical composition of claim 381, the conditioning agent of wherein said metazoan adenylyl cyclase suppresses the metazoan adenylyl cyclase.
385. the pharmaceutical composition of claim 381, the conditioning agent activation metazoan adenylyl cyclase of wherein said metazoan adenylyl cyclase.
386. the pharmaceutical composition of claim 381, the conditioning agent of wherein said metazoan adenylyl cyclase has significant anti-metazoan effect to infectious metazoan.
387. the pharmaceutical composition of claim 381, the amount of the metazoan adenylyl cyclase conditioning agent that is wherein given does not suppress metazoal growth.
388. the pharmaceutical composition of claim 381, the amount of the metazoan adenylyl cyclase conditioning agent that is wherein given can significantly not killed metazoan.
389. the pharmaceutical composition of claim 381, wherein said metazoan adenylyl cyclase is CO 2/ HCO 3/ pH responsive type.
390. the pharmaceutical composition of claim 389, wherein said conditioning agent influence is infected the metazoan adenylyl cyclase to CO 2Reaction.
391. the pharmaceutical composition of claim 389, wherein said conditioning agent influence is infected the metazoan adenylyl cyclase to HCO 3Reaction.
392. the pharmaceutical composition of claim 389, the reaction of metazoan adenylyl cyclase to pH infected in wherein said conditioning agent influence.
393. the pharmaceutical composition of claim 381, wherein said metazoan adenylyl cyclase are III class adenylyl cyclase.
394. the pharmaceutical composition of claim 381, wherein said infection is caused by the metazoan of anti-one or more anti-metazoan agent.
395. the pharmaceutical composition of claim 381, wherein said patient is a plant.
396. the pharmaceutical composition of claim 381, wherein said patient is an animal.
397. the pharmaceutical composition of claim 381, wherein said patient is a bird.
398. the pharmaceutical composition of claim 397, wherein said bird are poultry.
399. the pharmaceutical composition of claim 381, wherein said patient is a fish.
400. the pharmaceutical composition of claim 381, wherein said patient is a Mammals.
401. the pharmaceutical composition of claim 400, wherein said Mammals are domestic animal or pet.
402. the pharmaceutical composition of claim 401, wherein said domestic animal is selected from ox, pig, sheep and horse.
403. the pharmaceutical composition of claim 401, wherein said pet is selected from dog and cat.
404. the pharmaceutical composition of claim 400, wherein said Mammals is behaved.
405. the pharmaceutical composition of claim 381, the conditioning agent of wherein said metazoan adenylyl cyclase can significantly not suppress patient's adenylyl cyclase.
406. the pharmaceutical composition of claim 381, the conditioning agent of wherein said metazoan adenylyl cyclase is optionally with respect to patient's adenylyl cyclase.
407. the pharmaceutical composition of claim 381; the conditioning agent of wherein said metazoan adenylyl cyclase is enough to realize to infecting metazoal therapeutic action with respect to the selectivity of patient's adenylyl cyclase, and can not regulate patient's adenylyl cyclase toxigenicity.
408. the pharmaceutical composition of claim 381, the inhibitor of wherein said adenylyl cyclase are selected from small molecules, fit and RNA interfering.
409. the pharmaceutical composition of claim 381, wherein said metazoan is selected from: taeniasis suis (Taenia solium), taeniasis bovis (Taenia saginata), fish tapeworm (Diphyllobothrium latum), Echinococcus granulosus (Echniococcus granulosus), schistosomicide (Schistosomiasis), liver fluke (Clonorchis), pinworm (Enterobius), whipworm (Tichuris), roundworm (Ascaris), hookworm (Ancylostoma), quasi-colubriformis (Strongyloides), Trichinella spiralis (Trichinella), Anisakid nematode (Anisakis), Wuchereria (Wuchereria), filaria volvulus (Onchocerca), Loa loa (Loa), dragon nematode (Dracuncululs) and bow roundworm (Toxocara).
410. the pharmaceutical composition of claim 381, the inhibitor of wherein said adenylyl cyclase is selected from KH7.102, KH7.109, KH7.112, KH7.114, KH7.117, KH7.118, KH7.150 and combination thereof.
411. further comprising, the pharmaceutical composition of claim 381, described pharmaceutical composition give one or more anti-metazoan agent.
412. the pharmaceutical composition of claim 381, wherein said conditioning agent transmits in pharmaceutically acceptable vehicle.
413. the pharmaceutical composition of claim 381, wherein said composition are oral dosage form.
414. the pharmaceutical composition of claim 381, wherein said composition are parenteral dosage form.
415. a method for the treatment of the patient by the protozoal infections of the mediation of the protozoon adenylyl cyclase among the patient, described method comprises regulates protozoic adenylyl cyclase.
416. a method for the treatment of the patient by the fungi infestation of the mediation of the fungi adenylyl cyclase among the patient, described method comprises the adenylyl cyclase of regulating fungi.
417. a method for the treatment of the patient by the metazoan infection of the mediation of the metazoan adenylyl cyclase among the patient, described method comprises regulates metazoal adenylyl cyclase.
418. a method that suppresses protozoic adenylyl cyclase, described method comprises: protozoon is contacted with the compound that suppresses protozoic adenylyl cyclase.
419. a method that suppresses the adenylyl cyclase of fungi, described method comprises: fungi is contacted with the compound of the adenylyl cyclase that suppresses fungi.
420. a method that suppresses metazoal adenylyl cyclase, described method comprises: metazoan is contacted with the compound that suppresses metazoal adenylyl cyclase.
421. the method in the growth of external control protozoon, described method comprises makes protozoon contact with the conditioning agent of protozoon adenylyl cyclase.
422. the method at external control fungal growth, described method comprise fungi is contacted with the conditioning agent of fungi adenylyl cyclase.
423. the method in the growth of external control metazoan, described method comprises makes metazoan contact with the conditioning agent of metazoan adenylyl cyclase.
424. method of identifying the selective modulator of eukaryotic pathogens adenylyl cyclase; described method comprises: test described conditioning agent at one or more people's adenylyl cyclases; test described conditioning agent at the eukaryotic pathogens adenylyl cyclase, and measure the relative selectivity of described conditioning agent described adenylyl cyclase.
425. the method for claim 424, wherein said pathogenic agent are fungi.
426. the method for claim 424, wherein said pathogenic agent are protozoon.
427. the method for claim 424, wherein said pathogenic agent are metazoan.
428. a method that helps eukaryote in growth in vitro, described method comprises the activator that gives described biological adenylyl cyclase.
429. the method for claim 428, wherein biology is a fungi.
430. the method for claim 428, wherein said biology are protozoon.
431. the method for claim 428, wherein said biology are metazoan.
432. a method for preparing fungal metabolite, described method are included in the fungi of fermenting in the fermention medium that contains fungi adenylyl cyclase conditioning agent, separate fungal metabolite then from fermention medium.
433. the method for claim 432, the conditioning agent of wherein said fungi adenylyl cyclase make described fungi be in thread state basically effectively.
434. the method for claim 432, the conditioning agent of wherein said fungi adenylyl cyclase make described fungi be in non-thread state basically effectively.
435. the method for claim 432, wherein said fungi adenylyl cyclase is CO 2/ HCO 3/ pH responsive type.
436. the method for claim 432, wherein said fungi are selected from aspergillus citricus (Aspergillus citricus), aspergillus niger (As.niger), Aspergillus nidulans (As.nidulans), aspergillus oryzae (As.oryzae), flavus (Aspergillus flavus), aspergillus citricus (As.citricus), Aspergillus awamori (As.awamori), terreus (As.terreus), onion aspergillus (A.alliaceus), (A.atroviolaceus), Aspergillus candidus (A.candidus), carbon black aspergillus (A.carbonarius), Aspergillus carneus (A.carneus), rod aspergillus (A.clavatus), Fructus Fici aspergillus (A.ficuum), Aspergillus fumigatus (A.fumigatus), huge aspergillus (A.giganteus), methylene-succinic acid aspergillus (A.itaconicus), Neurospora (A.kiliense), honey aspergillus (A.melleus), Aspergillus ochraceus (A.ochraceus), Aspergillus parasiticus (A.parasiticus), nipa palm aspergillus (a.phoenicis), aspergillus rugulosus (A.rugulosus), saitox aspergillus (A.saitoi), Aspergillus sojae (A.soyae), Aspergillus tamarii (A.tamarii), Aspergillus wentti (A.wentii), short stalk mould (Au.pullulans), peachiness top spore (Acremonium persicinum), branch top spore mould (Acremonium chrysogenum), Calcarisporium arbuscula (Calcarisporium arbuscula), (Chaetomium gracile), endothia parasitica bacterium (Cryphonectria parasitica), Java penicillium (Eupenicillium javanicum), (F.coccophilum), the lanthanum element is to sickle-like bacteria (Fusarium solani), Fusarium oxysporum (Fusariumoxysporum), geotrichum candidum (G.candidum), (Mortiella ramannianua), (Mortierella vinaceae), (Mu.Circinelloides), pink colour bread mould (N.crassa), (Nectria lucida), (Penicillium vitale), (Penicillum decumbens), tangerine ash mould (Penicillium aurantiogriseum), Penicllium chrysogenum (Pe.chrysogenum), (P.amagasakiense), (P.baculatum), Penicillium citrinum (P.citrinum), Du Pont's mould (P.dupontii), penicillium funiculosum (P.funiculosum), Penicillium griseofulvum (P.griseofulvum), grey rose penicillium (P.griseoroseum), (P.isariiforme), citrus mould (P.italicum), penicillium jensenii (P.jensenii), (P.lilacium), yellowish mould (P.luteum), have a liking for loose mould (P.pinophilum), penicillum requeforti (P.roqueforti), letter mould (P.simplicissimum), not whole mould (P.turbatum), the shape mould (P.vermiculatum) of wriggling, rhizopus arrhizus (R.arrhizus), Rhizopus oryzae (Rhizopus oryzae), rhizopus stolonifer (Rhizop.stolonifer), snow-white head mold (R.niveus), (Rhizomucor miechei), Rhizomucor pusillus (R.pusillus), little spore root Mucor (R.microsporus), rice black root Mucor (R.meihei), Sclerotinia sclerotiorum (Sclerotinia libertiana), long shoot wood mould (T.longibrachiatum), Trichodermareesei (T.reesei), viride (Trichoderma viride), (Tolypocladium geodes), porous wood mould (T.inflatum) and many spores wood mould (Trichoderma polysporum).
437. the method for claim 432, wherein said fungal metabolite are enzyme.
438. the method for claim 432, wherein said fungal metabolite are microbiotic.
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